Curry Lab

Biophysics Section
Division of Cell and Molecular Biology
Department of Life Sciences
Faculty of Natural Sciences

News

Apr 2013:
First Calicivirus VPg structures

This paper was a long time in the making but we have finally reported the first solution structures of Calicivirus VPg proteins - for feline calicivirus and murine norovirus. There are interesting differences between the two, all the more surprising given their conserved roles in the initiation of translation and RNA replication.

Nov 2012:
Protease work bears hollow fruit

Back in 2007 we showed that mutations in the 3C protease of foot-and-mouth disease virus (FMDV) could be used to attenuate the enzyme activity. These reduced activity mutants have proved valuable in efforts to express synthetic virus capsids, which are translated as a polyprotein that has to be processed by co-expressed 3C. This latest paper (from a large collaborative group) reveals that the yields of 'synthetic FMDV capsids' are much greater if mutant rather than wild-type 3C is used for processing.

Jun 2012:
Eoin's and Gabriela's first paper

Congratulations to Eoin and Gabriela who have published their first paper - a report of the first crystal structure of a murine norovirus protease. This also the lab's first paper on a calicivirus protein (we have more in the works) and the first time we have published in the open access flagship, PLoS ONE.

Apr 2012:
Congratulations to Amar

Well done Amar who, following a testing viva at the end of February, has completed his PhD thesis: "Investigating the protein and RNA interactions of the polypyrimidine tract binding protein: high resolution structures with implications for the regulation of alternative splicing." The first paper from his work was published last December, but there should be more to come!

Amar has now moved to a postdoctoral position in Leicester with Richard Bayliss - we wish him every success.

Dec 2011:
First crystal structure of PTB

Thanks to great work by Amar and Olga we have just published the first crystal structure of the polypyrimidine tract binding protein (PTB) in Structure. Not only that, the construct used for the analysis was a chimera that fused a PTB-binding peptide from Raver1 to the 2nd RNA recognition motif (RRM) of PTB and allowed us to determine the structure of the complex. This fills in much needed detail from our initial analysis of PTB-Raver1 interactions which we reported back in 2006.

Dec 2011:
DemoJam

Back in October I got the chance to participate in a video project for the Royal Institution who have just launched a new online video channel. The video, a pilot called DemoJam was a light-hearted show-and-tell format involving myself and two other scientists demonstrating and talking about their work. It was somewhat nerve-wracking since the recording was made in front of a live audience but seemed to pass off OK. I talked about using X-ray crystallography to look at virus structure, using a child's toy as a prop...

Nov 2011:
Impact of the REF?

In his first real 'column' Stephen reflects on the upcoming Research Excellence Framework, the system that will be used to determine the quality of UK science so as to determine how research funding will be disbursed by HEFCE.

May 2011:
The best seminar?

It was Stephen's turn this month to give the Divisional seminar. By the wonders of modern technology, you can see it too. The talk started out with an ambitious synopsis of our recent work, and then took an unexpected (?) turn.....

May 2011:
Rapid data collection

Gabriela, Eoin and Stephen went to the Diamond synchrotron on 6th May to collect data on crystals of the protein that Gabriela has cloned, expressed, purified and crystallised. We did the data collection on beamline I04-1 and were very impressed by the speed with which the Pilatus detector recorded diffraction images - as you can see in this short video .

Mar 2011:
New student: Xulin Liu

Xulin Liu is studying for a Masters in virology at Imperial and has joined us for a six-month project to work on Calicivirus translation - as part of our ongoing collaboration with Dr Ian Goodfellow.

Jan 2011:
New student from Sweden

Gabriela Baeza is working towards a Masters os Science in Biochemical Engineering at Linkoping who has joined the lab for a few months to do her final year project. Her work will help to take our investigations into Calicivirus replication in a new direction.

Jan 2011:
Blog post selected for Open Lab 2010

Stephen was very pleased to learn that a blog post he wrote about one of his first experiences in amateur astronomy, was selected for inclusion in Open Laboratory 2010, an anthology of the best science writing on blogs from 2010. Fifty winning entries were selected by a panel of science bloggers from over 900 entries.

This is the third year in a row that Stephen's posts have been included in the Open Lab anthology - making a nice hatrick!

Nov 2010:
New student in the lab

Nan Jia is working towards an MRes Structural Biology and has opted to join our group to help continue our work on the FMDV protein that Trevor investigated for his PhD. We have come a long way but are looking to extend our structural and functional studies on an important part of the virus replication machinery.

Nov 2010:
Latest paper on HSA

Our latest paper on the crystallographic analysis of the ligand-binding properties of Human Serum Albumin (HSA) has just appeared in the Journal of Structural Biology.

The paper reports work that accumulated over a number of years from two PhD students, Ali Ryan and Jamie Ghuman, and one postdoc, Patricia Zunszain. Between them they produced seven co-crystal structures of different dansylated amino acids bound to albumin. The study is useful since these dansylated compounds are fluorescent and have been used for many years as convenient markers for the principal drug binding sites on HSA. Now, for the first time, we can see exactly where and how they bind.

Jun 2010:
I'm a scientist, get me out of here!

No, I haven't signed up for some awful TV show. But I have volunteered to participate in an online event that may be equally humiliating. Starting on Mon 14th June, I will be fielding questions from eager science students at schools around the country. Along with four other scientists, I will be hoping to impress them with my wit and knowledge because starting in week two, the students get to vote for their favourite scientist and day by day one of us will be evicted!

You can follow the action in the Imaging Zone (we are all interested in imaging techniques), or see my answers to the various questions here.

Lastly, here is a fun Spot the Difference puzzle I created for the children who we are talking to in the competition.

Update:If you check in on the Imaging Zone, you will see that I was lucky enough to emerge victorious! See here for the full story.

May 2010:
Latest Paper

Trevor's PhD work on the 2C protein from foot-and-mouth disease virus has just been published in the Journal of Biological Chemistry. This is the first paper from our work on this protein, which plays an important but poorly characterised role in the replication of viral RNA during infection.

The results show that 2C is an ATPase that can also bind RNA - consistent with its presumed but untested role as an RNA helicase, an enzyme that can separate strands of duplex RNA. We have shown for the first time that 2C can form hexameric rings in the presence of ATP and RNA, which is just the sort of structure that one would expect of some helicases.

April 2010:
New project student

Marie-Laure Parsy, who is taking the MRes in Structural Biology has joined the lab for her second project rotation. Her project will be to work with Trevor to develop an innovative approach to crystallising an interesting viral enzyme that we are working on.

March 2010:
Congratulations to Dr Sweeney

Having submitted his thesis in January, Trevor had his viva voce exam on Thu 11th March, conducted by Professor Martin Ryan (St Andrews University) and Dr Bernadette Byrne from Imperial. He emerged smiling and newly doctored!

A paper based on his thesis work, which has shed new light on a fascinating and much-studied viral enzyme, is now in the works.

Feb 2010:
New project student

Ayodele Omnisore has just joined the lab for his second project on the MRes in Biochemical Research. Ayo's project will be to work alongside Trevor to look at the expression of an important co-factor of a viral enzyme that we have been studying for some time now.

Feb 2010:
Communicating science

Stephen was invited by The Biochemist magazine to write about science and the new media. He took it as a cue to write about the impact of blogging and Twitter on science, to show how these new Web 2.0 tools can be used to tell a more colourful story about what really happens in science labs. The finished article was published in the Feb 2010 issue. You can find it here.

Jan 2010:
Trevor submits

Just over 3 months after sitting down to write in earnest, Trevor has finished his PhD thesis. The photo shows him proudly leafing through his newly bound thesis which has just been submitted.

It provides a detailed account of the work that he has been doing on a very interesting viral protein over the past couple of years. All will be revealed in a forthcoming paper which Trevor is now working on.

Jan 2010:
Structure of a protease-peptide complex published

Our latest paper has just been published in the Journal of Molecular Biology. It reports our determination of the crystal structure of the 3C protease from FMDV in complex with a peptide substrate. This is the first time such a structure has been solved for a picornavirus 3C protease. It reveals in glorious detail the interactions between the protease and the peptide that are responsible for specific cleavage between the P1 and P1′ amino acids (see figure).

Nov 2009:
Alumni Lecture

Last month I gave an evening lecture to a group of College Alumni. In my talk, titled Wrestling with an invisible enemy, atom by atom, I gave what I hope is a pretty accessible account of our work on the structure of the 3C protease from foot-and-mouth disease virus.

You can watch it too if you're interested by clicking on the link on the left.

Oct 2009:
New project student

Adrian Buckroyd has joined the lab for his first project on the MRes in Biochemical Research. He will be helping us to investigate some interesting new aspects related to how the polypyrimidine tract binding protein interacts with protein partners in the cell.

Sept 2009:
Two new review articles

We have had two new review articles published online in recent days. The first, which appears in Biochem. Biophys. Acta considered the various ways in which proteins specifically recognise the 5′ and 3′ ends of RNA. We contributed to this area with our structural analysis of La-RNA complexes last year, but there are many other interesting examples.

The second was devoted to structural analysese of human serum albumin (HSA) and was published in Drug Metabolism and Pharmacokinetics. This summarises the work done by ourselves and other labs to dissect the molecular basis of drug interactions with this abundant protein. I have also gone to some lengths in the review to detail the methods that are needed to investigate this tricky protein by X-ray crystallography.

July 2009:
Well done Ardi!

Congratulations to Ardi who not only scored an impressive 1st in his Biochemistry degree but went one better by winning the prize for the best undergraduate research project. This was for the work on PTB-raver1 interactions that he did alongside Amar and Olga in the lab. We wish him all the very best in his future research career.

June 2009:
New Paper

Just published in Molecular Cell, a new study probing the mode of interaction of the polypyrimidine tract binding protein (PTB) with an internal ribosome entry site (IRES) from an RNA virus. The investigation was initiated and driven by Richard Jackson's lab at Cambridge; we were able to help out with the structure-based design of the PTB mutants that were engineered to map the contact points on the protein and RNA.

May 2009:
New Students

Ardiyanto Liaunardy-Jopease (Ardi) joined us in May as a final year undergraduate working with Amar on methods to enhance the solubilty of PTB constructs.

He was joined by two new MRes students. First Wilfred Wu, from the MRes Structural Biology program, who will be working with Jingjie to investigate cis/trans-cleavage by an important viral protease.

And then at the very beginning of June we were joined by Joanna Young,from the MRes in Biochemical Research. Joanna will be working alongside Eoin to study the properties of a key protein in calicivirus RNA replication.

April 2009:
Podcast

Listen to Stephen being interviewed about our work on the 3C protease from foot-and-mouth disease virus by Meera Senthilingam on the Diamond Light Source podcast (Episode 2). The interview starts at about 12m 30s in and lasts about 7 minutes. If you've seen the video, you may recognise the story.

March 2009:
Going up the wall

In early March we took some time out one afternoon to test our heads for heights...! Thanks to Trevor and Gurdeep's expertise, no-one came to harm and indeed, I think everyone actually enjoyed themselves...

Click on the link on the left to see some of the photos.

Jan 2009:
Blogging success

Having finally dipped my toe in the blogosphere with my Reciprocal Space blog on Nature Network I am pleased to report that one of my pieces from last year has been selected for inclusion in an anthology of the best science blogging of 2008. My article, on thermodynamics, dealt with the colourful contributions to science of one Count von Rumford. See here for the full list of winning entries. The book is available from Lulu, priced very reasonably!

Dec 2008:
A structure at 1.4 Å!

This doesn't happen every day. Last weekend Amar, Trevor and myself took the crystals that Amar and Olga had been working on to the EMBL/DESY synchrotron at Hamburg. And we were delighted to find that they diffracted to at least 1.4 Å, which is a hew lab record for high resolution data collection. Our previous best was a La dataset collected by Olga to 1.85 Å (published this June - see below).

The resulting maps are stunning (see image) and reveal incredible detail. OK, in many cases there is no need to get to such high resolution when looking at biological macromolecules but every once in a while it's nice to be able to actually see the zig-zag in the density tracing out a lysine sidechain. Everybody worked hard on the project and has a smile on their face today!

Nov 2008:
New Masters Students

Gurdeep Minhas joined us from the MRes in Structural Biology, while Juree Hong is a student from the MRes in Biochemical Research. Both will be working on proteins from the foot-and-mouth disease virus, helping to develop our research program in new directions.

Oct 2008:
New PhD Students

This is slightly late but the arrival of October saw an influx of new talent into the lab, in the shapes of two new PhD students. Amar Joshi and Eoin Leen, who both worked with us previously in their rotation projects, have signed up for the long haulto help advance our work on projects related to translation initiation.

Amar will continue the work he started on PTB, while Eoin, who previously worked on FMDV 3C protease, is now going to help us delve further into the structural biology of caliciviruses.

Nov 2008:
Inaugural Lecture

Well, the 26th November has come and gone and, having been made a Professor last year, Stephen has now delivered his inaugural lecture—My date with density: making mountains out of molecules. Happily the event passed off very smoothly and a good time was had by all (including the speaker, who had been feeling rather tense, right up until the talk started!)

Sept 2008:
Making a Movie

Stephen will be attending the EU-FMD meeting on The Global Control of FMD - Tools, Ideas and Ideals. The conference organisers asked participants to come up with videos to explain their research on foot-and-mouth disease so we have stepped up to the plate and produced a short film about our work on the FMDV 3C protease.

Click on the image on the right to see the video. It explains how we are using X-ray crystallography to examine the protease structure and lay important groundwork for the development of antiviral drugs. This is an ongoing effort. Hopefully you will approve of our very high production values...!

Now also available (in higher quality) on Vimeo.

Update (21-10-08): We are very pleased to report that our video won the prize for best video (judged by popularity on YouTube). Thanks to all our viewers!

Aug 2008:
Congratulations Dr Roqué-Rosell!

And then it was Núria's turn to be put through her paces and she passed with flying colours in August. Núria, who was mainly supervised by Prof. Robin Leatherbarrow, worked on our joint project to investigate substrate and inhibitor specificity of the 3C protease from foot-and-mouth disease virus. She produed some very valuable reagents during the course of her PhD work that will be featuring in upcoming publications!

June 2008:
Congratulations Dr Ryan!

Following a thorough viva exam by Drs Ulrich Kragh-Hansen (Aarhus) and Kate Brown (Imperial), Ali emerged smiling having successfully defended his PhD work on serum albumin. His project involved cloning and expression of mammalian albumins for drug binding studies. Using crystallographic methods his work also revealed the structural details of the interactions of drug-site markers and diagnostic reagents to the human protein. Relieved that it was all over, Ali phoned his Granddad with the good news...

June 2008:
Olga's paper published in Structure

Our structural study on La-RNA interactions (first trailed in February - see below), which is based largely on crystal structures of the N-terminal fragment of La complexed with four different RNA oligomers has now been published in the June issue of Structure.

June 2008:
New paper: HSA-ligand complexes

Our latest structures of HSA complexed with bilirubin and fusidic acid are about to be published in the Journal of Molecular Biology. The manuscript was accepted today (3rd June), just over 6 weeks after submission which is a pretty fast turn-around.

The paper opens an interesting new chapter in our analysis of the binding of endogenous compounds to this versatile protein since this is the first structural analysis of bilirubin, a toxic breakdown product of haem, bound to its primary transporter. Our investigations provides some rather surprising results that we hope will stimulate further work in this area.

May 2008:
Techniques Workshop: Protein-Ligand Interactions

The Imperial College Centre for Structural Biology held its second techniques workshop on 21st May - this time devoted to methods for measuring protein-ligand interactions.

The workshop offered six short presentations from local experts on different methods for analysing ligand binding to proteins, including fluorescence, BIAcore, isothermal titration calorimetry, ELISA and NMR. As you can see from the picture, the subject matter (as well as the excellent refreshments) got people talking afterwards!

Further details and downloads of the presentations can be found here.

April 2008:
PhD progress

Congratulations to Ali who submitted his PhD thesis on drug interactions with human serum albumin on Friday 4th April after three and a half years of hard work! All that's left to do now is to write up some papers and mug up for the viva...

And congratulations are due also to Jingjie! She has has just found out that she is to receive a prestigious Overseas Research Student (ORS) award, which will help to fund her PhD studies.

Febr/March 2008:
Group retreat

At the very end of February, we took some time away from the lab to enjoy the delights of Derbyshire... and were surprisingly lucky with the weather!

Click on the link on the left to see some of the photos.

Feb 2008:
New crystal structures of La-RNA complexes to be published in Structure

The latest installment of our structural analysis of the human La protein is now in press. The crystallographic component of the work, which as led by Olga, has produced the structures of four different complexes of the N-terminal domain of the La protein with RNA. Becasues the crystals were so small the data were collected on the microfocus beamlines at the ESRF (many thanks to the support staff there!).

This study is part of our collaboration with Sasi Conte's group at Kings and has revealed a surprising degree of plasticity in the ways that the protein grips the different RNA molecules. The results mark an important advance in our understanding of the specificity of La for the RNA molecules that it binds in the cell (mostly Pol III transcripts with UUU sequences at their 3′ ends). They also show that we crystallographers need to be careful about interpreting the impact on our structural results of contacts between the molecules in our crystals.

Dec 2007:
SAXS data collection trip to Hamburg

Four of us - Stephen, Olga, Jingjie along with Cyril (a postdoc from Sasi Conte's group at Kings) - went to Hamburg to do small-angle solution scattering (SAXS) experiments at EMBL/DESY. It was hard work (!): more-or-less non-stop from Friday afternoon to early Sunday morning collecting data from a variety of different samples - including RNA-binding proteins and viral enzymes.

The experiments are done in collaboration with Dmitri Svergun and friends at EMBL, Hamburg.

Nov 2007:
Crystallographic data collection at the Daresbury Synchrotron, UK

Ali and Stephen went to Daresbury for yet another data collection trip with human serum albumin crystals. This time we were looking to see if we could detect binding of a heavily iodonated compound that has been used as a diagnositc X-ray constrast agent in patients. The compound is expected to bind in one of the main drug binding sites on the protein.

The crystals performed well and allowed us to get a dataset at high resolution (2.5 Å). As you see on the right, the resulting maps show clear evidence of something interesting bound to the protein. The blue chicken-wire shows the electron density for the protein while the green (difference density) indicates where the compound is bound.

Sept 2007:
Structure of Ebp1 published in EMBO Journal

Ebp1 - (ErbB3 binding protein 1; also known as ITAF45) interacts with the IRES from foot-and-mouth disease virus to stimulate translation. We solved the crystal structure of the murine protein and were able to characterise the RNA-binding activity. Unexpectedly, the protein was found to use a lysine-rich C-terminal tail to bind RNA.

The paper appeared online in EMBO J. in August 2007 - just two weeks before a competing lab who solved the structure of human Ebp1. We're glad we didn't wait any longer before publishing...

18 May 2013
http://www.bio.ph.ic.ac.uk/~scurry/