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ISMB News


This page contains recent ISMB News items. Previous ISMB news items are available in the archive.

Latest ISMB Newsletter

The 13th ISMB Newsletter is available to download here: Summer 2017 news

 

August 2017

Report on 2017 ISMB Retreat

The report on the ISMB's 7th Biennial Retreat that took place on 29-30 June 2017 is now available to download here.

July 2017

Matt Colledge wins Poster Prize at Annual Circular Dichroism User Group Meeting

Congratulations to Matt Colledge, a PhD student in Prof Bonnie Wallace's group, who won the PCDDB poster prize at the Annual Circular Dichroism User Group meeting on 12th July 2017.

 

Prof Kaila Srai collaborative research links iron status to risk of heart disease

Low iron levels may increase risk of heart disease

People with low iron levels may be at greater risk of heart disease, according to a new study involving the ISMB's Prof Kaila Srai.

Researchers analysing genetic data have uncovered a potential protective effect of iron in coronary artery disease, suggesting that having a higher iron status reduces a person’s risk of coronary artery disease (CAD), a type of cardiovascular disease (CVD) where clogged arteries reduce the amount of blood reaching the heart.

CVD is a leading cause of death worldwide, according to the World Health Organization, resulting in more than seven million deaths a year.

Previous research has shown that iron status – the amount of the nutrient in the body – plays a role in CVD risk, but studies to date have provided conflicting results. While some studies have shown high iron status may have a protective effect, others point to high levels of iron increasing the risk of heart attacks.

Scientists have struggled to prove that systemic iron levels directly influence the risk of CVD because many other factors including age and gender can affect both, making it difficult to untangle the relationship between them.

Now, researchers from UCL and Imperial College London have used a method called Mendelian randomization to try to establish if there is a direct or causal link between levels of iron and the risk of CAD, revealing that those with lower iron status are at greater risk.

In the study, published in the journal Arteriosclerosis, Thrombosis, and Vascular Biology, researchers looked at the link with heart disease by using people’s genetic variation as a proxy for their iron status, revealing that having a high iron status reduces the risk of CVD.

Using genomic data from a public database, the team searched through data for more than 48,000 people to work out the impact of genetic variants on people’s iron status. They focused on three points in the genome where a single ‘letter’ difference in the DNA – called a single nucleotide polymorphism (SNP) – can slightly increase or reduce a person’s iron status.

When these SNPs were screened for in datasets including more than 50,000 patients with CAD, they found that those with the SNPs for higher iron status had a lower risk of CAD.

The researchers explain that the next step would be to validate the findings in a randomised controlled trial, where patients would be given either an iron supplement or a placebo and then followed up to see if the supplements have any impact on their risk of CVD.

If the findings are validated, it could mean supplementing people with low iron status would potentially offer a simple way to help them reduce their risk of CAD.

“Previous studies have suggested a link between iron levels and heart disease, but it has been difficult to pick this apart from other confounding factors,” said Dr Dipender Gill, a Wellcome Trust Clinical Fellow at Imperial and lead author of the study.

“As our genes are randomly allocated before we are born, their impact on our systemic iron status is less affected by the lifestyle or environmental factors that can confound observational studies.

“We have shown that having low iron status increases the risk of coronary artery disease, but this doesn't mean correcting that resolves the increased risk. What we have highlighted is a potential therapeutic target that we didn't know about before, and one that's easily modifiable,” said Dr Gill.

“Maintaining iron at an optimum level is very important as both low and high iron levels can lead to diseases,” added study co-author Professor Surjit Kaila Srai (UCL Biosciences).

 

June 2017

ISMB member promotions announced

Congratulations to the following ISMB members, who have received UCL promotions effective from 1st October 2017.

Dr Jamie Baker, Department of Chemistry: promoted to Reader in Chemical Biology
Dr Vijay Chudasama, Department of Chemistry: promoted to Reader in Organic Chemistry and Chemical Biology
Dr Flemming Hansen, Structural and Molecular Biology: promoted to Professor of NMR Spectroscopy
Dr Alan Lowe Structural and Molecular Biology: promoted to Senior Lecturer

May 2017

ISMB Commentary

Crossed Legs Shut Down Molecular Motor Dynein

New ISMB research has shed light on how a vital molecular motor, dynein, is switched on and off to help build the cell’s antenna.

Largely disregarded as a relic for much of the last century, the cilium has only recently gained its status as the cell’s sensory antenna. Cilia project from the surface of eukaryotic cells and process a variety of signals essential for development and survival. Some can also move with a wave-like motion to power cell swimming and fluid flow.

All cilia are built from a cylinder of microtubules. They grow by the delivery of tubulin and other cargoes to their tip via motor-protein-driven transport.

It has been known that a molecular motor called kinesin-II powers cargo movement to the tip of the cilium by “walking" along its microtubules. Importantly, the ciliary transport system is bidirectional, because the motor machinery and signalling molecules need to be recycled to the cell body. Thus, a second motor, dynein-2, is used to power return transport.

This raises a problem: how does dynein initially reach the tip of the cilium, before being unleashed to power the return journey?

Writing in Nature Structural & Molecular Biology, Toropova et al. now report that dynein naturally exists in a switched-off state, in which its two microtubule-binding “legs” are crossed. This shut-down conformation enables dynein to be transported as a passenger of kinesin-II in the the tip-ward direction. Strikingly, disruption of the leg-crossing interface switches on dynein motility, indicating how the motor is activated for the return transport to the cell body.

Defects in dynein and ciliary transport cause a variety of severe pathologies (see http://www.ciliopathyalliance.org), and a better understanding of these processes might lead to new avenues for treatment.

This research was funded by the Wellcome Trust and Royal Society.

Reference
Katerina Toropova, Miroslav Mladenov, Anthony J Roberts (2017) Intraflagellar transport dynein is autoinhibited by trapping of its mechanical and track-binding elements. Nat Structural & Molecular Biology doi: 10.1038/nsmb.3391 http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.3391.html

http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.3391.html
Legs-crossed


April 2017

Dr Joanne Santini shortlisted as finalist for BBSRC Innovator of the Year

Congratulations to Dr Joanne Santini on being a finalist in the BBSRC's Innovator of the Year competition.
The prize-winner will be announced at East Wintergarden in London on 24 May 2017.

March 2017

Dr Victoria Hale's paper on Malaria-infected blood cells published

Dr Victoria Hale, former PhD student with Prof Helen Saibil, has had her work on Malaria-infected blood cells published on PNAS online this month. The full paper can be read at the following link:
Parasitophorous vacuole poration precedes its rupture and rapid host erythrocyte cytoskeleton collapse in Plasmodium falciparum egress

 

Professor Helen Saibil to be made honorary doctor of the Faculty of Philosophy of the University of Helsinki

Congratulations to Professor Helen Saibil, who is to be conferred an honorary doctorate from the Faculty of Philosphy of the University of Helsinki.
The doctorate is in recognition of Professor Saibil's research having focused on "three major areas relevant to Helsinki University: the mechanisms of protein folding, unfolding and aggregation, host-parasite interactions in malaria and chlamydia, and the formation of membrane attack complexes". Professor Saibil will receive the doctorate at a Conferment Ceremony in May.

February 2017

International collaborative research visualises the natural defence force within the immune system

Immune System Defence Force Captured in Action on Microscopic CCTV
Source: Peter MacCallum Cancer Centre

An international scientific collaboration involving ISMB researchers and the Peter MacCallum Cancer Centre and Monash University (Melbourne) has visualised in microscopic detail how the natural defence force within our immune system attacks and destroys harmful invaders such as virus-infected and cancerous cells.

The research, published on 6 February 2017 in Nature Nanotechnology, deepens understanding of the critical role of the protein called ‘perforin’ in a functioning immune system, bringing us one step closer to new therapies with the potential to boost or inhibit its impact when required.

The ISMB's Professor Bart Hoogenboom (UCL Physics & Astronomy and London Centre for Nanotechnology) and Professor Helen Saibil (Birkbeck) used atomic force microscopy and electron microscopy to reveal precisely how a subset of white blood cells, called cytotoxic lymphocytes (or Killer T Cells), show remarkable efficiency in first perforating their victims and next injecting poisonous enzymes to rid the body of disease.

Using a form of microscopic CCTV, it was shown how perforin binds to the protective membrane that surrounds harmful cells. Professor Hoogenboom said: “Our immune system needs to drill holes in virus-infected and cancerous cells to get rid of them, but can’t buy such drills in a DIY shop. We have now shown how it self-assembles these drills on the spot by putting multiple perforin molecules together in ring-like structures, leaving tiny holes - just tens of nanometres in diameter.”

Associate Professor Ilia Voskoboinik, a lead co-author (Peter MacCallum Cancer Centre), said: “To kill virus-infected or cancerous cells, perforin must be quick and efficient. Our experiments in Melbourne show that patients who are born with impaired perforin may present with fatal failure of the immune system and also have a higher risk of developing blood cancers.

“This was entirely consistent with the microscopic data obtained in London, which shows that the effectiveness of perforin is greatly hampered even if only a small number of the perforin molecules are abnormal. This new understanding brings us one step closer to targeted therapies that can strengthen the body’s perforin-producing power to ward off disease. We could also inhibit its function to prevent the rejection of organ transplants, when accepting foreign tissue or cells can be instead life-saving.”

To film perforin in action, the scientists used atomic force microscopy in Professor Hoogenboom’s lab at the London Centre for Nanotechnology at UCL. This type of microscopy uses an ultrafine needle to feel rather than see perforin on a target membrane, similar to a blind person reading Braille. The needle repeatedly scans the surface to produce an image that refreshes fast enough to track how perforin molecules get together and cut holes in the membrane.

Initially, perforin appeared as a blur on these images. However, once a few perforin molecules together inserted into the membrane, they could be more clearly identified and shown to recruit more perforin to thus growing transmembrane pores.

By also recording static snapshots at higher resolution by using electron microscopy, Professor Saibil’s team succeeded in estimating, for each perforin assembly, the number of molecules at each stage of the process. This confirmed a change from loosely packed small perforin assemblies on the membrane to larger and more tightly bound transmembrane pores.

Perforin

Above: Schematic view of the immune synapse between a lymphocyte (top) and a target cell (bottom).
Perforin (blue) and granzyme (red) are delivered to the synapse from the lymphocyte membrane (top).
Perforin binds to the target membrane (bottom) and, following a ‘growing pore’ mechanism, forms transmembrane pores.
The pores allow the toxic granzymes to pass the target membrane, and trigger cell death. (Credit: Adrian Hodel, UCL) 

December 2016

ISMB Commentary

Let it RIP - the first virus-encoded global inhibitor of archaeal RNAP

In the pioneering days of molecular biology, the study of bacteriophage regulators has been invaluable for the understanding of the molecular mechanisms of transcription. A plethora of viruses infect members of the second prokaryotic domain of life – the Archaea - but little is known about the mechanisms of viral transcription, or the role of transcription in the host-virus arms race. Now an international team led by the ISMB’s RNAP laboratory have discovered and characterized the first virus-encoded global inhibitor of archaeal RNAP transcription. The first author Carol Sheppard says ‘We undertake a multidisciplinary structural and functional characterisation of ORF145 to unravel its role in transcription regulation. Our results demonstrate that the protein (i) directly binds to RNAP with high affinity, which (ii) prevents the formation of transcription pre-initiation complexes (PICs), (iii) represses abortive and productive initiation, and (iv) represses transcription elongation. We propose a mechanism by which ORF145 is wedged into the DNA binding channel of RNAP and locks the otherwise flexible clamp into one fixed position. In agreement with its in vitro characteristics, the homologous expression of ORF145 in Sulfolobus is highly toxic. Based on its properties we name ORF145 RNAP inhibitory protein, RIP for short. Our detailed understanding of RIP’s biological function still leaves room for improvement, but RIP likely serves the virus by suppressing the activation of the Sulfolobus solfataricus type IIIb CRISPR system – keeping the virus ‘under the radar’ of the host defences’. This research project is a typical example of a successful multidisciplinary effort requiring expertise in biochemistry, biophysics, structural-, computational- and microbiology, and would not have been possible without the single molecule FRET expertise from the Grohmann lab (an ex-postdoc at the ISMB RNAP lab, now professor in Regensburg) and the crosslinking-mass spectrometry expertise provided by the Rappsilber lab in Edinburgh.

The study was published in Nature Communications on November 24th 2016 (https://www.ncbi.nlm.nih.gov/pubmed/27882920).

RIP1 RIP2

 

Prof Bart Hoogenboom awarded Royal Microscopial Society medal

Congratulations to Professor Bart Hoogenboom of the London Centre for Nanotechnology (LCN) on being awarded a Royal Microscopial Society (RMS) Medal for outstanding progress made in the field of scanning probe microscopy.

The medal series recognises and celebrates individuals who have made outstanding contributions to the field of microscopy across the life and physical sciences. Professor Hoogenboom is recognised for the development and application of scanning probe microscopy to a wide range of scientific areas throughout his research career, for his group's development of AFM methodology and data analysis to probe inside the channel of nuclear pore complexes and its starting of a programme of real time imaging of membrane degradation of antimicrobial peptides and pore forming proteins, and for his pivotal role in setting up the LCN.

Of the award, Professor Hoogenboom said, "I am of course extremely honoured to receive the RMS Medal, noting that a lot of the credit belongs to a great team of researchers, including my own group and various collaborators who have facilitated our access to a wide range of interesting and important biological research areas."

Professor Hoogenboom will be presented with the medal and will give a talk at mmc2017, the Microscience Microscopy Congress which takes place in Manchester from 3-6 July 2017.


Dr Kristine Arnvig awarded Microbiology Society prize

Congratulations to Dr Kristine Arnvig, on receiving the ‘Most Promising Science Prize’ from the Microbiology Society at the EMBO ‘Tuberculosis 2016’ conference at the Institute Pasteur in Paris, France in September.

Dr Arnvig’s team investigates the role of riboregulation - small RNAs and riboswitches - in the pathogenicity of Mycobacterium tuberculosis. The prize was awarded for an MRC-funded project, ‘DrrS, a DosR regulated small RNA in Mtb’ that is supported by Dr Alexandra Moores and Mr Stefan Schwenk.

November 2016

Dr Andrew Martin appointed as expert advisor to the WHO INN committee on the naming and description of antibody-based drugs

Congratulations to Dr Andrew Martin on his appointment to the WHO INN committee. The World Health Organization (WHO) International Nonproprietary Names (INN) committee provides unique generic names for drugs that are globally recognized and are public property. The INN 'Recommended Names' lists are available from the INN web site and include chemical structure information on drugs as well as their names. As well as small-molecule drugs, INNs are provided for biologics including antibody-based drugs. Many INNs adopt a naming convention and, in the case of antibodies, all INNs end with a '-mab' stem. This is preceded by a substem to indicate the source of the antibody (e.g. '-u-' for human, '-o-' for mouse, '-xi-' for chimeric or '-zu-' for humanized) and that is preceded by another substem indicating the general target (e.g. '-tu-' for tumour, '-li-' for immune system and '-vi-' for viral targets). Before that, up to two syllables are used as a unique name. Thus 'trastuzumab' represents a humanized antibody against a tumour target, 'infliximab' indicates a chimeric antibody targeting the immune system and 'palivizumab' a humanized anti-viral antibody. INNs are normally requested during clinical trials and antibody-based drugs are becoming increasingly popular: approximately half of the INNs requested are now for biologics and half of those (i.e. 25% of the total and currently over 100 per year) are antibodies. Of course many of these fail during trials and do not make it to the clinic.
Dr Andrew Martin has been appointed to the INN expert committee to advise on the naming of antibody-based drugs and on the documentation of the structure of the drugs.

Prof Bonnie Wallace selected as member of the BBSRC pool of experts

Congratulations to Professor Bonnie Wallace, who will be joining the Biotechnology and Biological Sciences Research Council (BBSRC) Pool of Experts. Members of the pool help to assess research grant proposals and identify the highest quality research for investment.


September 2016

ISMB Symposium student blog competition

Congratulations to 3rd year ISMB PhD students Harshira Patani, Pedro Tizei, Millie Pang and Tanya Prentice who will be awarded prizes for their entries in the blogging competition that took place at the 2016 ISMB Symposium.
Details about the competition and the prize-winning blog pieces can be read here on the ISMB website.

Prof Bonnie Wallace elected as Fellow of the Biophysical Society, USA

Congratulations to Prof Bonnie Wallace on being elected as a Fellow of the Biophysical Society. This follows her election as fellow of the British Biophysical Society earlier in the year.

August 2016

Dr Stefan Howorka receives EPSRC grant

Congratulations to Dr Stefan Howorka on being awarded a grant of £506,710 in July 2016 from the EPSRC for the project Minimal DNA Nanopores for Electrical Sensing of Proteins.

Dr Flemming Hansen receives Leverhulme Trust research grant

Congratulations to Dr Flemming Hansen on being awarded £198,009 over 36 months for the project Exploring the Conformational Sampling and Motions of Side Chains in Proteins.

July 2016

Prof Peter Rich receives Peter Mitchell Medal at EBEC 2016

Congratulations to Professor Peter Rich, who will be awarded the Peter Mitchell Medal at the 19th EBEC meeting in Italy in July, when he presents the opening plenary lecture.

Shining Light on Membrane Proteins Symposium

Shining Light on Membrane Proteins, a symposium with 16 UK and international speakers, will take place on Wednesday 10th August 2016 from 09:30 -18:00 in Birkbeck Lecture Room B33. For further details including the programme, please visit: http://webspace.qmul.ac.uk/rwjanes/Symposium.htm The event is expected to be oversubscribed and seating is limited, so parties wishing to attend should please send an email to ‘PCDDB@mail.cryst.bbk.ac.uk’ before 22nd July 2016 in order to reserve a place prior to the event being opened to the public.

Prof Bonnie Wallace elected an Honorary Member of the British Biophysical Society

Congratulations to Prof Bonnie Wallace, who is among the 3 scientists to be elected as honorary members of the British Biophysical Society for 2016.

June 2016

Prize Winners at the ISMB Graduate Symposium

The ISMB's 2016 Graduate Symposium took place at UCL on 2nd and 3rd June.
Congratulations to PhD students Jenny Booker and Matt Colledge of Prof Bonnie Wallace’s group, who won the prizes for best 1st year talk and best 3rd year talk respectively, and to Adrian Hodel, PhD student in the London Centre for Nanotechnology, who won the prize for best poster at the Symposium.

Anaïs Cassaignau awarded Bogue Research Fellowship

Congratulations to Anaïs Cassaignau in Prof John Christodoulou's group, who has been awarded a Bogue Research Fellowship to spend 5-6 months in 2017 with Professor Joseph Puglisi, Stanford University, to develop single-molecule fluorescence methods to study co-translational folding processes on the ribosome in real-time.

4th Ion Mobility Mass Spectrometry Special Interest Group Meeting

The 4th Ion Mobility Mass Spectrometry special interest group meeting will be held on Thursday 14 July 2016 within the ISMB at Birkbeck.
It will showcase recent advances in, and applications of, IM-MS research. The plenary lecture will be delivered by Prof Edwin De Pauw from the University of Liège.

Registration closes on Friday 30th June.

May 2016

ISMB Commentary

Structural Snapshots of Proteins being synthesised on Ribosomes

The ribosome is the molecular machine responsible for protein biosynthesis within all living systems. During protein translation, within the ribosome’s catalytic centre, the nascent polypeptide chain is assembled, and progressively emerges from the ribosomal exit tunnel. Upon its exit, the highly dynamic nascent polypeptide chain has its first opportunity to begin to gain structure, which is a critical requisite for its biological activity. A detailed molecular understanding of how a nascent polypeptide chain acquires its native structure and avoids misfolding during translation, is absent.

To explore the structure of emerging nascent polypeptide chains, we developed a strategy using E.coli in which we generated translationally-arrested ribosomes of a tandem pair of immunoglobulin domains, to capture the process of biosynthesis of FLN5 in a series of discrete steps. In this way, we have the capacity to monitor the FLN5 nascent polypeptide chain as it progressively elongates and exiting the ribosome, and where it has its first opportunity to acquire tertiary structure. In addition, by manipulating E.coli growth conditions, we have selectively, isotopically-labelled the nascent chain within the 2.4 MDa ribosomal complex, using labelling strategies that specifically target either the peptide backbone (using 15N labelling) or individual side chains of methyl-containing amino acids (13C labelling). This enabled us to apply NMR spectroscopy to probe exclusively both the structural and dynamical features of the ribosome-bound nascent chain at a residue-specific level (Cassaignau AME et al, Nat Prot 2016), generating fingerprint information. Each step of biosynthesis, therefore reports upon a structural snapshot of the elongating nascent chain (Fig. 1).

Using each of our structural snapshots, we have been able to define the stage during biosynthesis at which the nascent chain can form native structure. Surprisingly, we have found that the nascent chain does not fold immediately once the amino acid sequence is available, despite the isolated protein being capable of forming native-like structure, when 90% of its sequence is present (Fig. 2). Instead, there is a “delay” (or offset) for folding of ca. 44 amino acids and by also taking into account that that the ribosomal exit tunnel can hold ca. 32 amino acids, it appears that the ribosome actively prevents folding from taking place. This is likely to be a mechanism by which aberrant folding processes are mitigated, to encourage efficient folding, especially in multi-domain protein systems, in which a high degree of similarity (> 40%) between domains can have a deleterious effect on folding (Cabrita et al, Nat Struct Mol Biol 2016).

We then used NMR data of the dynamic nascent chain as structural restraints within molecular dynamics simulations (Fig. 3) to generate a 3D structural ensemble of a globular nascent chain tethered to its parent ribosome; the structures show a number of contacts made with several ribosomal proteins near the exit tunnel which is perhaps providing some early insights of the mode by which folding is being modulated by the surface of the ribosome. Our parallel studies - where we have also examined by NMR ribosome-nascent chain complexes a folding incompetent protein, alpha-synuclein, an intrinsically disordered protein – show that even without the complication of folding needing to take place, the nascent chain inherently makes transient interactions the ribosomal surface in a sequence-dependent manner implicating important residue types (Deckert A et al, PNAS, 2016). Molecular chaperones, such as the ribosome-associated protein, trigger factor which first interacts with the nascent chain, also have the capacity to shape nascent chain dynamics and folding processes further, and we observe such modulations even in the case of non-substrate such as alpha-synuclein.

Our NMR studies of RNCs are thus enabling us to describe at high-resolution, the earliest events of structure acquisition that is possible for nascent chains as they emerge from the ribosome. The functionality of the ribosome appears to extend beyond that of a molecular machine of protein biosynthesis and its 3D architecture is emerging as a framework for modulating downstream processes of structure acquisition, and increasing a means of quality control.

Prof John Christodoulou

References

A strategy for co-translational folding studies of ribosome-bound nascent chain complexes using NMR spectroscopy. Cassaignau AME, Launay HMM, Karyadi ME, Wang W, Waudby CA, Deckert A, Robertson AL, Christodoulou J, Cabrita LD. Nat Prot 2016. In press

A structural ensemble of a ribosome-nascent chain complex during cotranslational protein folding. Cabrita LD, Cassaignau AM, Launay HM, Waudby CA, Wlodarski T, Camilloni C, Karyadi ME, Robertson AL, Wang X, Wentink AS, Goodsell LS, Woolhead CA, Vendruscolo M, Dobson CM, Christodoulou J. Nat Struct Mol Biol. 2016 23(4):278-85. doi: 10.1038/nsmb.3182.

Structural characterization of the interaction of α-synuclein nascent chains with the ribosomal surface and trigger factor. Deckert A, Waudby CA, Wlodarski T, Wentink AS, Wang X, Kirkpatrick JP, Paton JF, Camilloni C, Kukic P, Dobson CM, Vendruscolo M, Cabrita LD, Christodoulou J. Proc Natl Acad Sci U S A. 2016 113(18):5012-7. doi: 10.1073/pnas.1519124113.


Dr Bart Hoogenboom, Dr Alan Lowe and Prof Helen Saibil receive BBSRC grant

Congratulations to Dr Bart Hoogenboom (PI), Dr Alan Lowe and Prof Helen Saibil who have been awarded a responsive mode grant of £458,449 for the project Integrated Microscopy approach to Protein Assembly on and in Membranes.

Dr Matthew Gold wins BCA prize

Congratulations to Dr Matthew Gold on winning an early career prize from the British Crystallographic Association (BCA). The prize was awarded by the Biological Structures Group of the BCA and sponsored by Rigaku. Matt collected the prize at the BCA Spring Meeting held in Nottingham in April, where he presented his structural work on a signalling protein complex that regulates synaptic strength.

Dr Andrea Townsend-Nicholson receives BBSRC grant

Congratulations to Dr Andrea Townsend-Nicholson on being awarded a research grant in May 2016 for 'Development of an Experimental-Computational Integrated Technology to Address the Residence Time of GPCR Ligands'.

April 2016

ISMB collaborative project receives BBSRC grant

Congratulations to Prof Bart Hoogenboom (PI), Prof Helen Saibil and Dr Alan Lowe on being awarded a BBSRC contribution of £458,449 for their project, 'Integrated Microscopy Approach to Protein Assembly On and In Membranes.

Dr Matthew Gold receives BCA early career prize

Congratulations to Dr Matthew Gold, who has won an early career prize from the British Crystallographic Association (BCA), awarded by the Biological Structures Group and sponsored by Rigaku. Matt collected the prize at the BCA Spring Meeting held in Nottingham in April, where he presented his structural work on a signalling protein complex that regulates synaptic strength.

Dr Vijay Chudasama receives UCLU Student Choice Teaching Award

Congratulations to Dr Vijay Chudasama, who was awarded the Outstanding Researcher Development prize at the UCLU Student Choice Teaching Awards in April 2016 (voted for by UCL students).

March 2016

Doris Quay receives FEMS Travel Award

Dr Doris H.X. Quay was a Commonwealth International PhD Scholar in the Department of Biological Sciences, Birkbeck, supervised by Prof Nicholas H. Keep and Dr Sanjib Bhakta and successfully completed her PhD in 2015.
Congratulations to Doris on receiving a prestigious FEMS International Travel Award to attend and present a research poster on structure and function of two key proteins in bacterial dormancy at the Gordon Research Conference on New Antibacterial Discovery and Development 2016 in Italy (13th - 18th March 2016).

Chris Earl receives BCA award

Chris Earl, a finalist Wellcome Trust PhD student in Dr Renos Savva’s group, won the prize for Best Poster at the British Crystallographic Association (BCA) Winter meeting on 16th December 2015.
The poster, entitled Structural studies of a viral uracil-DNA glycosylase essential for DNA maintenance and replication, showed how the group solved the crystal structure of the Kaposi's sarcoma-associated uracil-DNA glycosylase (kUNG) in complex with DNA in order to investigate the conformation of DNA presented by kUNG and the potential link of this conformation with a non-canonical role of kUNG in viral DNA replication.
The award was presented by John Helliwell (emeritus professor at the University of Manchester).

February 2016

Cross-country collaboration discovered novel hybrid molecules to reverse antimicrobial resistance in TB

Mycobacterium tuberculosis is a pathogenic bacterium which is responsible for causing tuberculosis (TB), and every year, nearly 9 million healthy individuals get newly infected resulting in 1.5 million deaths. Treatment of the disease involves a harsh course comprising of a cocktail of antibiotics over a period of many months. To complicate matters further, multi-, extensively- and even totally-drug resistant tuberculosis (MDR-, XDR-, TDR-TB) cases make the disease, virtually impossible to treat as most drugs in use today are ineffective against them.

The urgent need for new, shorter therapeutic regimens and new classes of drugs active against these drug-resistant bugs drove the cross-country collaboration among researchers based at Birkbeck, University of London, King’s College London, University College London, Durham University in the UK (UK-team led by Dr. Sanjib Bhakta and Dr. Daniele Castagnolo) and at Siena University in Italy (Italy-team led by Dr. Fabrizio Manetti) to develop potential anti-TB drugs. This inter-disciplinary effort between scientists specialised in chemical synthesis and molecular microbiology resulted in the exhaustive evaluation of a library of hybrid pyrrole derivatives for their anti-tubercular properties against MTB and MDR-TB strains. The library of molecules were synthesised based on the common features of the compounds BM212 and SQ109, both of which generated tremendous interest in the anti-infective drug discovery discipline, as they were found to be potent anti-mycobacterial agents.

Thus it was a remarkable feat to achieve five novel hybrid molecules that showed anti-tubercular activity against MTB at ≤1.0 mg/L, two of which proved to be highly active against MDR-TB clinical isolates as well. One of the potent anti-tubercular derivatives showed low eukaryotic cell-toxicity, to be a lead candidate for preclinical development. In addition, four compounds showed potent whole-cell drug efflux inhibition in mycobacteria, and thus turning to be prospective multi-drug resistance reversal agents. These promising drug candidates are now the main premise of a patent application being submitted by UCLB and more information on these compounds and their biological properties can be found in the latest issue of the peer-reviewed, highly reputable Journal of Medicinal Chemistry. http://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.6b00031


Novel_Hybrid

 

Prof Peter Rich delivers Sir Hans Krebs Memorial Lecture and is awarded Peter Mitchell Medal

Prof Peter Rich delivered the prestigious 2016 Sir Hans Krebs Memorial Lecture at Sheffield University in February.

Prof Rich has also recently been awarded the Peter Mitchell Medal by the European Bioenergetics Conference organisation, which he will receive when presenting the opening plenary lecture of the 19th EBEC meeting in Italy in July.

January 2016

Andy Lau wins Poster Prize

Congratulations to BBSRC LIDO rotation student Andy Lau (working with Steve Perkins and Lindsay McDermott) for winning a £100 poster prize for his poster 'Molecular modelling of multiple fatty acid binding pockets in human zinc-α2-glycoprotein' at the 12th Zinc UK meeting held at Ophthalmology on Friday 4th December.

December 2015

Featured Publication

Structure of a bacterial type III secretion system in contact with a host membrane in situ

Many bacterial pathogens of animals and plants use a conserved type III secretion system (T3SS) to inject virulence effector proteins directly into eukaryotic cells to subvert host functions. The purified core complex of the T3SS that is embedded in the bacterial envelope has been extensively studied by single particle analysis and individual protein domains by X-ray crystallography. Despite this, there is still much to discover about the mechanisms of these critical virulence machines, particularly how effectors are recruited to the T3SS in the bacterial cytoplasm and the nature of the interaction with the host membrane. However, the T3SS components mediating these steps are lost during the biochemical isolation of the core complex. We have shown that the intact infectious Chlamydia trachomatis elementary body is small enough to visualise by cryo-electron tomography [Nans A et al (2014)]. This allowed us to visualise the T3SS complexes which are present in an array on one hemisphere of the bacterial surface and to examine the bacteria and the T3SS in contact with a host cell membrane in situ for the first time in any system. Now, we have extended this work by using subtomogram averaging to derive the intact structures of the chlamydial T3SS in the bacterial envelope and in contact with the host cell membrane at ~3.5nm resolution. A comparison of these two averaged structures revealed a marked (~4nm) compaction of the complex spanning the bacterial envelope occurs when the tip of the T3SS apparatus contacts the host cell membrane. This compaction is coupled to the stabilisation of the recently discovered sorting platform-ATPase complex in the bacterial cytoplasm that engages effector substrates. Our findings reveal the first structure of a complete bacterial T3SS from a major human pathogen engaged with a eukaryotic host, and reveal striking ‘pump-action’ conformational changes in the T3SS that underpin effector injection.

This work was funded by the Wellcome Trust.

Nans A, Kudryashev M, Saibil HR and Hayward RD (2015) Structure of a bacterial type III secretion system in contact with a host membrane in situ.

Nature Communications 6: doi:10.1038/ncomms10114 http://www.nature.com/ncomms/2015/151211/ncomms10114/full/ncomms10114.html Nans A, Saibil HR and Hayward RD (2014) Pathogen-host reorganisation during Chlamydia invasion visualised by cry-electron tomography. Cell Microbiol 16:1457-1472

Pathogen-host reorganisation during Chlamydia Invasion

 

November 2015

2nd BPHR Symposium hosted by the ISMB

The 2nd London Postgraduate Research Symposium on Bacterial Pathogenesis and Host Response (BPHR) took place on Friday 27 November at Birkbeck College. The event was hosted by the ISMB for 2015, following the inaugural event at Imperial College in 2014.
The meeting was co-organised by three final year ISMB PhD students Eleanor McMahon (ISMB Wellcome Trust programme in Structural, Computational and Chemical Biology), Charlotte Ford and Oliver Martin (both ISMB MRC programme in Macromolecular Machines of Biomedical Significance) all from Dr Richard Hayward’s group.

Professor Carolyn Moores joins BBSRC pool of experts

Congratulations to Professor Carolyn Moores, who will be joining the Biotechnology and Biological Sciences Research Council (BBSRC) Pool of Experts for 2016.
Members of the pool help to assess research grant proposals and identify the highest quality research for investment.

Dr Richard Hayward receives MRC Research Grant

Congratulations to Dr Richard Hayward, who has received a MRC grant to continue research of the type III secretion system from Chlamydia in collaboration with Professor Helen Saibil. The grant will fund 1 PDRA for three years.

Professor Carolyn Moores receives Worldwide Cancer Research Grant

Congratulations to Prof Carolyn Moores, who has received a Worldwide Cancer Research grant for the project Elucidating Inhibition Mechanisms of Mitotic Kinesin Motors using State-of the-Art Cryo-Electron Microscopy. The grant will will fund 1 post-doctoral researcher (Dr Julia Wenger) for 3 years.

Dr Andrea Townsend-Nicholson receives LIDo Industrial CASE studentship

Congratulations to Dr Andrea Townsend-Nicholson, who has been awarded a LIDo Industrial CASE studentship with Evotec (UK) Ltd, to develop a binding affinity calculator for G protein-coupled receptor drug discovery programmes.
The advertisement for the studentship will be posted in the near future, with an application deadline of 22 January 2016.

October 2015

Dr Maya Topf receives MRC Grant

Congratulations to Dr Maya Topf, who was recently awarded a Research Grant for the project An integrative approach to deciphering the entry process in Herpesviruses. The grant is for 3 years to run until the end of September 2018.

Professor Helen Saibil receives Senior Investigator Award

Congratulations to Professor Helen Saibil who has been awarded a Wellcome Trust Senior Investigator Award for the project, Molecular and cellular mechanisms of protein aggregation and toxicity in models of neurodegeneration, which will run until the end of March 2020.

Professor Elizabeth Shephard receives Wellcome Trust funding

Congratulations to Professor Elizabeth Shephard, who has received a Wellcome Trust Pathfinder Award for the project, Novel metabolite based therapeutics for improved cholesterol, glucose and reduced weight gain.

Professor Kaila Srai appointed Chair of ILSI Expert Group

The ISMB's Professor Kaila Srai has been appointed to Chair one of the International Life Sciences Institute, Europe (ILSI) Nutrient Intake Optimisation Taskforce expert groups, entitled "Interations of Micronutrients with Other Constituents of the Food Matrix ­ What Could Be the Adverse Health Consequences of Changes in BioAvailability?"

The objectives of the Expert Group are available from the ILSI website: Nutrient Intake Optimisation Expert Groups

September 2015

Vitor Pinheiro receives ERASynBio Consortium Grants

Congratulations to Dr Vitor Pinheiro on two successful applications to ERASynBio. ERASynBio is an initiative of international funding agencies working together to promote the robust development of Synthetic Biology and to structure and coordinate national efforts and funding programs.

Grant 1: InvivoXNA - Orthogonal biosystems based on phosphonate XNAs (Top ranked application of the 57 received on the call)
For this grant, Dr Pinheiro is the consortium leader of a 6-lab team involving partners in the US, France, UK and Belgium.
The goal of the project is to create the first XNA system in vivo based on phosphonate XNAs. The total budget of the project is £1677k, of which Dr Pinheiro has been awarded £570k from September 2015 to August 2018, to fund 1 PDRA and 0.5FTE Technician.

Grant 2: TNAepisome - Design and Synthesis of a Bio-orthogonal Genetic System Based on Threose Nucleic acids In Vivo
For this grant, Dr Pinheiro is part of a 5-lab team involving partners in the US, Spain and France. Although the ultimate goal is the same as the invivoXNA, the methodology, target polymerase, chemistry and route to bring the XNA into the cells are all different. This was a slightly smaller consortium, with a total budget of ~EUR1.7M, of which Dr Pinheiro has been awarded £460k from October 2015 to September 2018 funding 1.5FTE technicians.

The BBSRC has encouraged both consortia to collaborate, making UCL the hub for both projects.

August 2015

UCL Biosciences Senior Academic, Research and Teaching Fellow Promotions 2014-15

Congratulations to the following ISMB members who have been successful with academic and research promotions within the UCL Division of Biosciences for 2014/15. The promotions are effective from 1 October 2015.

ISMB Graduate Symposium Prize Winners

Congratulations to Francesco Carbone and Saba Ferdous (both in Andrew Martin's group), who won the best presentation award and best poster awards respectively at the 2015 ISMB Graduate Symposium held in July 2015.

July 2015

ISMB Commentary

A “missing link” in the evolution of transcription machineries

One of the hallmark features of eukaryotic cells is the multiplicity of RNA polymerases (RNAPs). All eukaryotic cells contain three RNA polymerases (RNAP I, RNAP II, and RNAP III) responsible for the transcription of rRNA, mRNA and tRNA, respectively. The core of RNAPI-III transcription machineries shows strong conservation testifying their common evolutionary origin. Other components of the transcription machineries, however, were reshaped throughout evolution to a degree that their origin and functional basis remain obscure.

In their latest paper, Finn Werner’s RNAP lab at the ISMB identified and characterised a new basal transcription factor termed TFEα/β from a distant relative of eukaryotes, the archaeon Sulfolobus solfataricus. Like its RNAPII homolog TFIIE, TFEα/β acts as a basal transcription factor stabilizing the transcription preinitiation complex. Both TFIIE and TFEα/β enhance the initial melting of DNA at the transcription start site as a prerequirement of transcription initiation and consequently TFEα/β stimulates transcription in vitro. Structurally, however, TFEα/β shares some features with its RNAPIII counterpart, the subcomplex hRPC62/39. The most prominent one is a newly discovered iron-sulfur cluster that is essential for the dimerization of TFEα/β. The identification of the iron-sulfur cluster was a collaborative effort of three ISMB groups with EPR-studies in Chris Kay’s lab and native mass spectrometry in Konstantinos Thalassinos’ lab. The combination of several techniques was essential to unambiguously determine the type of cluster being present in TFEα/β. Based on the structural analysis a minimal TFEα/β complex could be identified. Surprisingly, two highly conserved domains of TFEα/β appear to be dispensable for transcription stimulation in vitro, suggesting that these domains become essential in the cellular context where transcription is initiated on chromatinised, topologically restraint DNA.

The new findings deepen our understanding of the evolution and diversity of transcription machineries in archaea and eukaryotes.

Sulfolobus solfataricus TFEα/β interacts with the RNAP via the clamp and stalk modules
Sulfolobus solfataricus TFEα/β interacts with the RNAP via the clamp and stalk modules. The subunit composition of TFEα/β  provides a evolutionary and structural basis for the gain and loss of domains that characterise the evolution of its counterparts in the RNAPII and III transcription machineries.

Original Article: Archaeal TFEα/β is a hybrid of TFIIE and the RNA polymerase III subcomplex hRPC62/39, by Fabian Blombach, Enrico Salvadori, Thomas Fouqueau, Jun Yan, Julia Reimann, Carol Sheppard, Katherine L Smollett, Sonja V Albers, Christopher WM Kay, Konstantinos Thalassinos, Finn Werner (2015): http://elifesciences.org/content/4/e08378

 

June 2015

Award Winning Students

Congratulations to Po-Jung Pao in Professor Steve Perkins' group who was awarded a Biochemical Society Travel Award to attend the ARVO meeting in Denver, Colorado, USA in 3-7 May 2015. Po-Jung was featured in a blog on the Biochemical Society web site.

Congratulations to Ka Wai (Gary) Fung and Orla Dunne, also from Prof Steve Perkins' group, who received prizes at the 15th European Meeting on Complement in Human Disease in Uppsala, Sweden in 27-30 June 2015. Ka Wai received the prize for best poster, for 'The bivalent and co-operative molecular mechanism of Factor H binding to a heparin-coated surface accounts for the onset of inflammatory diseases'. The poster explained how the major complement regulator factor H binds to heparin-coated surfaces on host cells. The poster will be presented as a talk at an ISMB Friday Wrap this Autumn 2015.
Orla won a prize for best abstract for her submission entitled, 'A dimerization site at SCR-17/18 in Factor H may explain its disease-causing mutations and a new mechanism for regulatory control'.

Finally, congratulations to Ms Sayoni Das from Prof Christine Orengo’s group, who received the prize for best poster at the Intelligent Systems for Structural Biology (ISMB/ECCB) Automated Protein Function Prediction SIG meeting in Dublin in July 2015.

 

Amandine Maréchal awarded 5 year MRC Career Development Fellowship

Congratulations to Dr Amandine Maréchal who was recently awarded a MRC Career Development Fellowship for the project Cytochrome C Oxidase: Structure, Function and Malfunction to run until May 2020.

May 2015

Dr Flemming Hansen wins Marlow Award

Congratulations to Dr D. Flemming Hansen on being awarded the 2015 Marlow Award from the Royal Society of Chemistry. The Marlow Award is in recognition of the most meritorious contributions to physical chemistry or chemical physics. Dr Hansen received the award for the development and application of NMR spectroscopy in understanding motions in biological molecules at atomic resolution. 

ISMB members awarded SLMS Teaching Team Award

The team behind the UCL Continuing Professional Development (CPD) course “Lab Techniques in Mammalian Cell Biology” have been awarded a Teaching Team Award by the UCL School of Life and Medical Sciences.

Prof Ivan Gout (Course Lead) and Prof Snezana Djordjevic (Course Director) from the Research Department of Structural and Molecular Biology at UCL and Josephine McNally (Marketing & Communications) from CPD hope to continue their success with further short courses they have in the pipeline.

April 2015

St Mary's School, Buckinghamshire wins 'Creative School of the Year' for "TB or not TB" collaboration with Dr Sanjib Bhakta

Congratulations to Dr Sanjib Bhakta and St Mary’s School, Buckinghamshire (http://www.stmarysschool.co.uk/) on winning the “Creative School of the Year 2015/16” award for their after-school “You Can initiative” Science Project 'TB or not TB' in collaboration with Birkbeck.

The School received a letter from Lord Erroll as well as an invite for them to receive the prestigious award from the House of Lords.

'TB or not TB' is an after-school science project uniquely designed by the Bhakta lab at Birkbeck in collaboration with Mrs Jo Kingston and Mrs Penny Baggott at St Mary’s School, Buckinghamshire, based on the lab's discovery of anti-TB activities in common non-steroidal anti-inflammatory drugs (NSAIDs) and a simple drug susceptibility testing (SPOTi) developed at the laboratory in Birkbeck. See news item from February 2015, below.

The “You Can initiative” project was run by a group of senior girls (Year 11) at St Mary’s School in 2014, funded by the British Institute of Technology and E-Commerce (BITE). As one of the many direct outcomes of the project, the participating students and their Science Teachers Mrs Baggott and Mrs Kingston organised a World TB Day public event in March 2015, at which they gave a group presentation on their laboratory findings with Dr Bhakta in front of a full house. Audience members included a panel of specialist researchers from University labs and local press.
In addition, the group of students created a short film capturing different steps in their project investigation in a very systematic and meaningful way to depict their progression to date.

March 2015

Early Career Research Award for Anthony Roberts

Congratulations to Dr Anthony Roberts, who has been awarded the 2016 'Early Career Research Award: Molecular Structure and Function' from the Biochemical Society.

The Early Career Research Awards are given to outstanding scientists in four different areas, with 'Molecular Structure and Function' as one of the categories in 2016. They recognise scientists for the excellence of their work and the profound impact their research has had on the scientific community and wider society.

The award to Anthony recognises "his research of the highest international standard focused on the structure and mechanism of cellular motor proteins”. His studies, which have relevance to neurological disease, have helped illuminate how one of the least understood motor proteins called dynein moves and is regulated. 

Anthony is invited to give the award lecture at a Biochemical Society conference during 2016, when he will be presented with the Early Career Research Award medal. His lecture will be published in Biochemical Society Transactions.

Anthony Roberts

Image credit: Janet Iwasa

February 2015

Dr Sanjib Bhakta to chair TB Summit at O2 Arena in March 2015

Dr Sanjib Bhakta will be chairing the TB Summit 2015 (24th – 26th March at O2 Arena, Greenwich peninsula, London) organised to commemorate this year's World TB Day.

This international summit organised by EuroSciCon will be in its third year in London. A meeting report will be published to a peer-reviewed journal, as in previous years.

Dr Bhakta will also be delivering a TB Day public lecture and jointly presenting an on-going Science Project with the Year-11 students of St Mary’s School, Buckinghamshire. The School won the “You Can Initiative Award 2014/15” from the British Institute of Technology and E-Commerce on “TB or not TB” led by Dr Bhakta. This project aims towards repurposing existing drugs to treat TB as well as to tackle antibiotic resistance in TB. Dr Bhakta recently wrote a review article entitled “Repurposing - a ray of hope in tackling extensively drug resistance in TB”, which is accepted for publication at the International Journal of Infectious Diseases for a special issue to be published on the World TB Day 2015, jointly organised by UCL-TB and LSHTM-TB.

Dr Bhakta is currently a Reader in Molecular Microbiology at the Institute of Structural and Molecular Biology, Birkbeck, University of London and Honorary Senior lecturer at three research departments of UCL (Research Department of Structural and Molecular Biology, Department of Infection and UCL-School of Pharmacy). He is also a Cipla Distinguished Fellow in Pharmaceutical Sciences and “Antibiotic Action Champion” Member of the British Society for Antimicrobial Chemotherapy. To find more information about Dr Bhakta and ISMB-Mycobacteria Research Lab’s TB research and outreach activities follow: https://www.facebook.com/pages/Dr-Sanjib-Bhakta-PhD-DPhil-Oxford/1402960816587288.

Bhakta_StMarys

January 2015

Dr Giulia Zanetti awarded 3 year Royal Society studentship

Congratulations to Dr Giulia Zanetti from the Department of Biological Sciences, Birkbeck, who has been awarded a PhD studentship by the Royal Society.
The studentship will run for 3 years from 1 March 2015, with research carried out towards the project, 'Mechanisms of Regulation of COPII-Mediated Procollagen Secretion'.

Vacancy: ISMB Lectureship in Infrared Spectroscopy

The ISMB is seeking applications to fill a lectureship in the field of Infrared Spectrosopy. We are particularly interested in (but not limited to) applications of the method to the investigation of biomolecular structures such as electron transfer proteins.

 

 

 

 

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