Under the Microscope: Kinesin Motors and Cancer.

This post was written first for the Birkbeck College events blog and is re-posted here with permission.

There are many different types of cancer but each is caused by the failure of a cell to control its normal healthy cell division.  Uncontrolled proliferation produces a cluster of cancerous cells, a tumour, often the first indicator of many cancer types.  Several prevalent cancer drugs target microtubules, which are used by the cell to orchestrate the intricate ballet of cell division, but disabling this machinery provokes various unpleasant associated side effects.  In this lecture, which was part of Science Week, Dr Carolyn Moores, of the Department of Biological Sciences at Birkbeck shared some exciting recent developments in her work which pave the way for new cancer drugs which are less toxic to the rest of the body.

To understand the size of the machinery under discussion, if a human body were amplified to fill the whole of Buckingham Palace, each cell would be approximately the size of a single grain of sand.  These cells need to replicate, both to grow and to repair normal wear and tear and this replication is a delicate and highly regulated process.  Dr Moores showed a video of a dividing cell, taken from a remarkable online library of cellular images.  This process starts with the separation of the chromosomes, the familiar four legged bearers of our DNA, of which there are 23 pairs in humans.  The chromosomes arrange themselves in the centre of a spindle-like framework, which then retracts in opposite directions, separating each chromosome into halves and grouping them into two new nuclei centres, ready for the division of the rest of the cell. 

An image of mitosis showing the microtubules (in green) in spindle formation and chromosomes (in blue) about to be divided

The dynamic spindle framework at the heart of this incredibly accurate mechanism is primarily composed of microtubules along with associated proteins including members of the kinesin family of molecular motors, which organise them.  Microtubules are made up of pairs of tubulin molecules, or dimers, each of which has a polar structure.  The dimers bind to each other both longitudinally, with opposites attracting so that the overall polarity is maintained, and laterally so that long thin stable cylinders are formed.  These cylinders can grow and shrink with great flexibility and at all lengths the cylindrical structure provides a frame which can withstand the tension required in pulling chromosomes apart.  Drugs that block the dynamics of microtubules can therefore block the ability of cells to proliferate, which is why they are used in chemotherapy.  Unfortunately, microtubules are also critical in healthy cell repair, as well as providing frameworks essential for cellular structure, organelle positioning and vital transport networks within the cell.

Kinesins are highly attractive as potential targets since each appears to operate primarily in support of one of the major microtubule functions, in which case an inhibitor could be designed to attack the cell’s ability to divide without affecting its other vital processes.

Kinesin proteins comprise several domains, one of which is the motor domain, responsible for the protein’s movement.   This motor binds to a microtubule and uses it as a track with a directionality given by its polarity.  It also binds ATP, the universal cellular fuel, which provides the energy required to move along the track.  This has been particularly well studied in kinesin 1, whose function is to transport cargo along the microtubules.  In a mechanism that Dr Moores compared to a child walking on his hands, each unit of cargo is transported by a linked pair of kinesin 1 molecules.  The molecules alternate so that one will bind to the microtubule and the energy source, ATP, and then its partner will displace it so that the motor effectively steps hand over hand along the microtubule track.  Structural studies of kinesin 1 bound to a microtubule show that a small linker region of each kinesin reacts with the polarity of the track to point and presumably inform the direction of travel.

Dr Moores’ group are studying kinesin 5, which combines into oligomers of four molecules and forms crosslinks between microtubules.  This has been shown to be essential to cell division in humans.  The structural studies have involved cryo electron microscopy which has given a 3D model of the motor domain of kinesin 5 bound to a microtubule, both binding ATP and without ATP present.  Electron microscopy is a technique much like ordinary microscopy except that an electron beam is used instead of visual light and this gives images at a molecular level.  This technique is covered in detail in the TSMB course, one of the options following PPS for students working towards an MSc.   I have included the link although current PPS students will not have access to the course material.  The fact that a fast freezing method is employed is extremely useful since biological samples are effectively viewed in solution, as they are in their natural state.  By fitting x-ray crystallography models, which give atomic level detail of smaller molecular configurations, into the 3D cryo electron microscopy models, an enormous level of detail is obtained.

Drugs that target kinesin 5 are currently in clinical trials and appear to be successful so far.  It would appear that the drugs interact with an on/off switch elucidated by Dr Moores’ team but at the moment the precise function of the on/off switch is not known.  PDB 1Q0B shows an example of an inhibitor bound to kinesin 5 at the loop which functions as a switch.  Work continues in this rewarding area of study with the aim of understanding the purpose of the on/off switch and consequently being able to design future cancer drugs which have even higher specificity and consequently better outcomes.

Dr Moores has written a section of the TSMB course covering structural investigation of kinesin 5.  Again, unfortunately, current PPS students will not yet have access to this link.  The piece is taken from the last section of TSMB, which showcases the application of the many different structural techniques covered in the course to the study of a wide variety of proteins.

More details of Dr Carolyn Moores’ work are available at http://www.bbk.ac.uk/biology/our-staff/academic/carolyn-moores/

Commemorating World TB Day: Drugs from Plants

This post was written first for the Birkbeck College events blog and is re-posted here with permission.

World TB Day is held on 24 March every year, to mark the day in 1882 when Robert Koch, one of the fathers of microbiology, first announced that he had discovered the cause of tuberculosis (TB) – the bacterium now known as Mycobacterium tuberculosis (link to the TB proteome page in PPS section 5). Over 125 years since its discovery, and despite billions of dollars of investment in drug discovery, this bacterium is still a killer. The World Health Organisation estimates that about two billion people are infected with latent tuberculosis; in 2010, the last year for which full figures are available, over eight million people became ill with active tuberculosis, and 1.4 million people died from the disease. Two factors help make TB particularly deadly: it often occurs in people infected with the HIV virus, where it is one of the major causes of death, and drug resistant forms are becoming more common. In January 2012, Nature reported the identification in India of so-called “totally drug resistant” (TDR) tuberculosis, resistant to all anti-TB drugs in general use.

 Image of Mycobacterium tuberculosis bacteria

Photo credit: Janice Carr, Centers for Disease Control and Prevention, USA

In 2012 at Birkbeck, World TB Day coincided with the start of the College’s annual Science Week. Dr Sanjib Bhakta, head of the Mycobacteria Research Laboratory in the Department of Biological Sciences, organised a well-attended symposium on tuberculosis and its treatment. Besides two scientific presentations, the symposium featured a short video, Tuberculosis: The Real Story, highlighting the views of people affected by TB in the UK, and a panel discussion led by the grassroots volunteer organisation Results UK on some of the political challenges raised by tuberculosis.

Both science lectures focused on plants as a source of potential new drugs for tuberculosis. Professor Franz Bucar from the University of Graz in Austria highlighted the extreme chemical diversity of compounds that could be extracted from plants, particularly as compared to those found in the average synthetic compound library. Plants have always existed alongside their own microbial pathogens and have evolved natural antibiotics to protect themselves. Our ancestors, before the dawn of scientific medicine, used plant extracts to treat infectious disease, often quite successfully. The sub-discipline of ethnomedicine involves “mining” these traditional or historical remedies for pure chemicals that can be developed as, or modified into, drugs.

Bucar described a European herb, elecampane or Inula helenium, which is known to have been used to treat lung disease in the sixteenth century. He explained how a complex mixture of natural products derived from this plant had been tested against mycobacteria. Compounds found to have anti-mycobacterial activity were extracted and purified. Other plants have also yielded useful lead compounds; extracts of bark from a small tree with the Latin name of Berchemia discolor have even been shown to inhibit multi-drug resistant strains of Mycobacterium tuberculosis at useful concentrations.

Discovering antibacterial products in plant extracts, however, is only a first step towards drug discovery. Even when natural products like these compounds are found to be selective for bacterial over human cells, it is necessary to discover their mechanism of action; to modify them to optimize their activity; and, since plant sources are often scarce and extraction processes costly, to determine methods of synthesizing them in the laboratory.

The second scientific presentation was given by Dr. Bhakta himself and described current work in Birkbeck’s Mycobacteria Research Laboratory in searching for potential drugs for TB. These are needed not only to combat resistant forms of the bacteria but to improve current treatment regimens for “standard”, drug-sensitive TB. This requires a combination of four drugs to be taken for two months followed by two drugs for another four months, and many patients, particularly poorer and less well educated ones, fail to complete such a long and complex regimen. This in turn can lead to the development of further resistant strains.

Ideally, new drugs are required that target proteins not targeted by existing drugs, as resistance will be harder to develop. Mycobacteria have extremely complex cell walls, unlike those of other types of bacteria; they are essential for the bacteria to survive, and the enzymes used to synthesise them have no equivalents in mammalian genomes. These enzymes, therefore, have many of the characteristics of excellent drug targets.  Bhakta and his group have been exploring ways to inhibit the synthesis of the peptidoglycan that is one of the most important constituents of that cell wall. This molecule has been described as the bacterium’s “Achilles heel”, but no drugs targeting its synthesis have yet entered the clinic.

Mycobacteria synthesise peptidoglycan via a series of enzymes known as ligases, each of which adds a new link to the growing peptidoglycan chain. Bhaka’s group has focused on one of these ligases, termed MurE. This enzyme is essential for the bacterium to survive and it is conserved in all Mycobacterium tuberculosis strains. Working in collaboration with Professor Nick Keep, also in the Department of Biology, Bhakta solved the structure of MurE (PDB 2XTA) and showed it to have an active site that could in theory, at least, be occupied, and blocked, by a relatively small, “drug-like” molecule. He and his co-workers are now searching libraries of natural products for compounds that might inhibit this enzyme. They have identified promising MurE inhibitors from plants endemic to both Colombia and China, and are synthesizing analogues of these compounds for further testing.

It is unlikely that the next generation of anti-tuberculosis drugs will include any unchanged natural products. It is extremely likely, however, that natural products will yield the “scaffolds” on which these desperately needed drugs may be built, and perhaps one of these will be generated from within Bucar’s or Bhakta’s groups.

Hello from a recent graduate of the Structural Molecular Biology MSc

Hello everyone.  My name is Jill Faircloth and, as the title suggests, I graduated from the MSc last year.  My plan is to become a freelance science writer and Clare has very kindly allowed me a voice on this blog.  I will be blogging from the Birkbeck Science week next week but first I thought I’d introduce myself.

I read Chemistry as an undergraduate but soon discovered that aspirations to a glorious research career were incompatible with my lab skills.  I therefore put on a suit and became a chartered accountant before moving to ICI and working my way up the finance ladder.  That’s where I was when I had my first child and I would have stayed but an opportunity arose in my husband’s career and we left for San Francisco for a couple of years.  This and the subsequent baby gave me (plenty) of time to realise that I couldn’t go back to the spreadsheets and I decided to follow my interest in structural molecular biology.

This took me to where you are now and, since it is March, and assuming the timetable hasn’t changed too much, you have just navigated symmetry and are now battling through the fascinating but rather dense protein lifecycle.  Since I know that it can be a little overwhelming when you’re in the middle of one of the lengthier sections, I thought I’d give you a quick heads up of what’s in store.  Section 9 is on molecular forces and has quite a different flavour from the rest of PPS.  There’s more physics to contend with but by the end of it the logic behind protein interactions is much clearer.  After that you’re into the home straight and what I found to be the most enjoyable part of the course.  The last 3 sections deal with how the function of a protein is dictated by its detailed molecular structure and by the interactions which are promoted or inhibited by that structure.  For me, this is where I could really get a sense of quite how remarkable the evolution of proteins is.  Various protein types are examined and used as examples of the elegance of mechanisms in which subtle molecular changes can trigger impressive macro consequences.  This is what the rest of the course has been building up to.

After that you will be out of the comparative comfort of working through the sections, with some of you performing the delicate balancing act of simultaneous revision and project work.  This is where I can offer you a few top tips from the previous class.  You should definitely get hold of at least 5 years of past papers.  Even if you don’t have time to work through them all, as you go through you will see that certain topics have a higher probability of featuring than others.  Also, don’t leave all of your work on the project until after the exam, particularly if you are new to HTML.  HTML takes a little time to crack, although a speedy way to do it is to look at the text of previous years’ projects and copy the bits for inserting titles, tables, pictures and links.  Another reason for getting some foundation research in early is that sometimes a key review paper may not be available online and, although the Birkbeck library is extremely helpful, there is a time lag in retrieving hard copies which you may not be able to accommodate in the time between the exam and the project submission.  Please don’t let these comments put you off.  Producing the project is hard work but is extremely satisfying as you get the scope to really engage with a subject in a way that there isn’t often time for during the coursework.  Speaking personally, it was the experience which inspired me to try my hand at science writing, hopefully the beginning of a shiny new career.

The other subject which may be on your minds is the choice of course for the second half of your MSc.  I chose TSMB on the basis that we were told by Prof Nick Keep that it was the best basis for a PhD and at the time I was labouring under the fond delusion that I would be able to attract sponsorship to do a part time PhD.  I have asked an old PPS colleague who chose PX for his opinions so that I could give you a brief student’s view of the choices on offer. 

TSMB is Techniques in Structural Molecular Biology.  It covers a myriad of techniques that are employed to decipher the molecular structure of proteins from the DNA technology employed to code the protein of interest, through the wet lab skills used to identify, isolate and prepare a sample to the physics of different methods of structure solution.  The sections consequently vary greatly in density and difficulty but the course has been thoughtfully structured so that the more demanding sections are interspersed with the lighter ones.  I found the course very interesting and indispensible for understanding structural biology literature.  I can definitely see why Nick said that it would be the best basis for a PhD although I should say that the consensus among the students that I used to chat with regularly was that it was more challenging than PPS.

PX is Protein Crystallography, which is where a crystal of a protein is obtained and x-rays are directed through it to produce a diffraction pattern.  This pattern can be interpreted to give the electron density of each non-hydrogen atom in a molecule and hence its structure.  This is a technique in which Birkbeck has an extremely strong reputation and consequently is a tempting course for anyone wishing to specialise.  My inside source reported that there was a good variety between sections and that on balance he found it slightly less demanding than PPS although I would have to say that his perception probably speaks to his non-biological background.  There is also the opportunity in this module to handle real data and solve a structure as a project. 

Being that I am over my 1000 word limit, I had better sign off.  I hope that one or two of these observations may be helpful and wish you all the best of luck with the rest of the course.

Beyond the Central Dogma

Biological information may be represented in different ways. The famous central dogma of molecular biology, as described by Francis Crick and others in the 1970s, states that "DNA makes RNA makes protein" (see this page in PPS section 6: Bioinformatics).. Nowadays, some exceptions to this simple statement of the single-direction flow of information are known, such as the synthesis of DNA molecules from a RNA template by the retroviral reverse transcriptases or the synthesis of telomeres by telomerase. However, it is very likely that early biology used a simpler molecular architecture. The "RNA World" hypothesis states that early life was based on RNA alone - the only molecule that is capable of both storing information and catalysing chemical reactions - and was only later superseded by  the DNA-RNA-protein world of today.

Such an RNA world would have relied on an ability of RNA molecules, or "ribozymes" to synthesise other RNAs following a template: another way of saying that in this world, each of the components of the "central dogma" would have been represented by a type of RNA. Phillip Holliger, a group leader in the Protein and Nucleic Acid Chemistry division of the MRC Laboratory of Molecular Biology, Cambridge, gave an interesting seminar to the Institute of Structural and Molecular Biology at UCL in early February in which he described his recent work exploring how the chemistry of this "RNA World" might have worked.

Holliger began by introducing the concept of a RNA replicase: an RNA sequence that can catalyse the extension of a RNA primer. No natural RNA replicases are known: if there was once such a primordial molecule, it has been lost in time. In order to understand the RNA replicase, therefore, it is first necessary to synthesise one.  In 2001, David Bartel and his group at MIT in Boston, Massachusetts, published a paper (Johnston et al. (2001), Science 292, 1319-25) describing a synthetic ribozyme that was able to catalyse the addition of over a complete turn of a RNA primer strand on a template sequence to a "reasonable" level of accuracy.  Holliger's group is one of several that have, since then, been making improvements to the basic replicase.

The work in the Holliger group has involved developing a technique known as compartmentalized bead-tagging (CBT)  for directing the "evolution" of a synthetic RNA polymerase. Put very simply, this involves using water-in-oil emulsions to select and isolate ribozymes from a library that had specific RNA primer extension properties. Observing that their original ribozymes had poor ribozyme-template-primer interactions, they generated a library of ribozymes with additional random 5' domains. Three rounds of CBT were needed to isolate a ribozyme named C19 that had improved RNA polymerase activity. Secondary structure prediction suggested that the new 5' domain of this ribozyme consisted of a short sequence complementary to the 5' end of the RNA template used in the experiments, followed by a hairpin domain. This sequence complementarity promotes the formation of a stable ternary complex between the ribozyme and the template and primer RNA strands thereby allowing processive synthesis of long RNA molecules. Further directed mutations have yielded a ribozyme (tC19Z) that can catalyse the synthesis of a RNA that is itself catalytic: a mini-version of a hammerhead ribozyme (link to PDB structure 1MME).. Holliger's group may still be quite a long way from generating a truly self-replicating molecule (which would have been necessary in a primordial RNA world) but they are making progress towards this goal.

This work can essentially be seen as "restricting" or "shrinking" the central dogma to one type of  information-containing macromolecule from three. Holliger and his group are now using similar techniques to try to "expand" the dogma by adding an extra branch, developing polymerases that can synthesise and reverse transcribe artificial poly-nucleotides based on unnatural building blocks not found in nature.  


Holliger's work on the ribozymes was published last year in the journal Science: Wochner et al. (2011), Science 332, 209-212. Click here to access this paper (login to Birkbeck e-library required).


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BCA Winter Meeting: Structures of Supramolecular Assemblies

The British Crystallographic Association (BCA) is a national organisation set up to support all types of crystallography in the UK. It is affiliated to the International Union of Crystallography and has five special interest groups, one of which, the Biological Structures Group, is devoted to the study, by crystallography, of proteins and other biological macromolecules. One of the Biological Structure Group's main activities is its annual Winter Meeting, which conventionally takes place just before the Christmas break. This is always well attended by students and post-docs; the speakers, however, are generally senior scientists presenting some of their most exciting recent research in protein structure.

The 2011 BCA Winter Meeting was held at the Diamond Light Source, the country's national synchroton facility (which is located at Harwell, near Didcot in Oxfordshire. When it opened in 1997 it was the largest scientific facility to be built in the UK for over thirty years. Synchrotons like Diamond generate highly intense, monochromatic (single-wavelength) beams of electromagnetic radiation that are used for many types of scientific experiment, including X-rays for crystallography. The theory behind how X-ray diffraction is used to solve the structuresof proteins is not covered in PPS, but it is in both the courses that can be taken for the second year of the MSc: fairly briefly in the general Techniques for Structural Molecular Biology course and very extensively in a specialist course.

This meeting took "Structures of Supramolecular Assemblies" as its theme and featured nine distinguished speakers, discussing complex structures, biological mechanisms and protein-protein interactions. And the first speaker was none other than the head of the Department of Biological Sciences at Birkbeck, Professor Gabriel Waksman. His ground-breaking work on the structure and mechanism of fibres that form at the outer membrane of bacteria such as E. coli to attach to the host cells has been discussed previously on this blog (e.g. in June 2011) and so will not be described in more detail here.

Waksman's talk was followed by two more describing proteins and protein complexes that are embedded in the membranes of bacterial cells. The first of these was given by Colin Kleanthous from the University of York, who described proteins involved in signalling through porins, proteins that form pores in the outer membranes of Gram negative bacteria. Porins were the first transmembrane proteins to be discovered where the membrane-spanning region forms a beta barrel rather than a bundle of alpha helices. Very many alpha-helical membrane proteins pass signals into cells from their environment, with the signal arising when ligand binding triggers the receptor to either dimerise or make a subtle change in its structure (conformation). Colicins are protein antibiotics that are synthesised by bacteria, often to kill very similar bacteria that occupy the same ecological niche. They do this by "parasitizing" the porins through which nutrients enter the target bacteria, a particularly difficult task as porins act as filters that generally allow only "nutrient-sized" molecules (less than about 600Da) to enter cells. Kleanthous described the structures and mechanisms of the "outer membrane translocation" domains of several colicins bound to porins; his group is now trying to solve the structures of intact colicin-porin complexes using both crystallography and electron microscopy.

Leo Sazanov from the MRC Laboratory of Molecular Biology in Cambridge then described the structure of respiratory complex I, which is embedded in the bacterial inner membrane.. This is the first enzyme in the respiratory chain, and it is found in mitochondria as well as bacteria: the respiratory complex I in human mitochondria has been implicated in the pathology of Parkinson's disease.  The bacterial enzyme complex is smaller and simpler than the human one and is often used as a model system. Sazanov and his group crystallised the complete complex from Thermus thermophilus, a "thermophilic" bacterium that can live in extremely hot conditions. Proteins from thermophilic bacteria are often more stable and easier to crystallise than their equivalents in other species. The complete structure was found to contain no fewer than 63 transmembrane helices, 14 in each of three similar subunits. Sazanov discovered that this protein's mechanism involves a quite substantial conformational change between its oxidised and reduced form; an analogy with coupling rods has led the protein to be described as the "steam engine of the cell". It featured, in similar terms on the front cover of the issue of Nature in which the structure was described (Efremov et al. (2010), Nature 465, 441-5).

Nature cover illustrating the structure of respiratory complex I

About 5% of all proteins in an "average" bacterium are synthesised in response to heat or other stress signals. Stresssosomes are large multi-protein complexes found in bacteria and that control this stress response through the release of another protein, known as the sigma factor. Rick Lewis from the University of Newcastle described how the overall structure of a stressosome from Bacillus subtilis has been solved by electron microscopy and structures of some of the individual components by crystallography.  He is using these structures to explore the mechanism through which the stressosome senses the presence of stress conditions. Although several pieces of the stress response pathway still remain to be discovered, his group has shown how the system could respond to differences in levels of light and oxygen (the latter through the presence of a globin domain in one of the stressome proteins), how it could regulate the production of diguanylate cyclase, and how the system is re-set through the action of a serine/threonine phosphatase (the structure of which was solved at Diamond).

Helen Walden of Cancer Research UK described how her group's structural studies are shedding light on the mechanism of a DNA repair pathway that is damaged in Fanconi anaemia, a rare genetic disorder that causes, among other things, a greatly increased susceptibility to one form of leukaemia. This repair pathway, which fixes cross-links in DNA, is triggered by the single ubiquitinylation of a DNA repair protein. (This is the fusion of a small protein known as ubiquitin with a target protein.) The process is triggered when cross-links cause DNA to stop replicating; the first step is the assembly, in the nucleus, of eight proteins into a "core complex" in the nucleus. The core complex then activates another protein, known as FANCL, and this catalyses the fusion of ubiquitin with the DNA repair protein, activating it. The structure of FANCL was recently solved in Walden's group by Ambrose Cole, who is now a post-doc at Birkbeck (PDB 3ZQS). Interestingly, the structure of this protein is not the beta-propellor that was predicted by sequence analysis; instead, it contains two domains similar to the ubiquitin conjugating enzyme UBC. Mutations that abolish ubiquitin binding are known to cause disease.

These are only a few highlights of  a fascinating day's science. Other, no less interesting, structures presented there included several viral proteins: the HIV integrase bound to some of its inhibitors, presented by Peter Cherepanov (Imperial College London); the nucleoprotein from the virus that causes Lassa fever, described by Chang-jing Dong (University of St. Andrew's); and the NS1 protein from the influenza virus, described by Phil Kerry, also from St. Andrew's

Structural Secrets of an Ancient Viral Plague

Research in Biological Sciences at Birkbeck, and several related departments at neighbouring University College London, is combined into the Institute of Structural Molecular Biology. The Institute holds a regular seminar programme - every Wednesday lunchtime during termtime - in which it invites excellent scientists, many with links to the colleges, to present their research. A few weeks ago, the seminar speaker was an electron microscopist, Sarah Butcher, who is based at the University of Helsinki in Finland. Her group has been investigating the structure of a virus that causes a very well-known disease: measles.

Measles has been known of for millennia. The disease (although of course not its cause) was first described in ancient Egypt. It is one of the most infectious viruses known, but people who encounter measles (if at all) as an unpleasant childhood affliction are often surprised to learn that it is a killer. About 164,000 people lost their lives as a result of measles infection in 2008, most from lingering immunosuppression rather than the acute infection. Most deaths occur in Africa and south Asia; a smaller epidemics have recently arisen in the UK when the MMR vaccination lost popularity over the MMR autism scare.

The measles virus is a paramyxovirus; an enveloped virus with a single strand of RNA as its genome, and closely related to the viruses that cause mumps, respiratory syncytial virus (RSV) infection and para-influenza in infants and children. It has two surface proteins and iis thought to attach directly to the membranes of the cells it infects via one of these.

Until recently, structural studies of the measles virus have been fairly limited. Many groups have studied it using an electron microscopy technique called negative staining, but that can only see the virus' surface. Structures of one intact measles virus protein and domains of three others have been deposited in the Protein Data Bank; the haemagglutinin (e.g. PDB code 2RKC); two separate domains of the phosphoprotein (1OKS and 2K9D) and a structure of fragments of two proteins simply called P and N bound together (1T60).

Sarah Butcher and her group used a technique called cryo-electron microscopy, which allows the interior of viruses to be visualised, to study the measles virus. Their results led them to focus on the matrix protein, which is thought to be important for the assemby of the virus (the protein coloured cyan in the images below). All previous models had placed the matrix protein covering the inner part of the viral membrane. What the Butcher group saw, however, was completely different. They could see a protein surrounding parts of nucleocapsid - the viral RNA and its associated, protective protein - and further analysis identified this as the matrix protein. The matrix binds tightly to parts of the nucleocapsid to make rod-like structures, and these fold into anti-parallel units that are somewhat remniscent of antiparallel beta sheets in proteins. This model suggests that the process of virus replication will be more complex and yield more potential drug targets than has previously been thought.

Two models for the organisation of proteins and RNA in the measles virus. Top: the old model, with the matrix protein (cyan) surrounding the virus coat. Bottom: the Butcher group model, with the matrix protein surrounding parts of the nucleocapsid. Figure credit: Proc. Nat. Acad. Sci. USA (2011)

Structures of proteins from other viruses, particularly HIV and influenza, will be covered quite extensively later in the PPS course. We don't study the technique used in this study, cryo-electron microscopy, in PPS but it is covered in one of the options for the second year of the PPS course, Techniques in Structural Molecular Biolog

Welcome to new students!

A warm welcome to the Principles of Protein Structure blog to all students who have just started studying Birkbeck's Principles of Protein Structure course!

I run this blog to link the material that you will be studying in the course to new research developments in the areas of protein structure and function and related aspects of biotechnology and medicine. Throughout the taught course (but more often in the later part of the course) I will post reports of recent developments. I might, example, report on talks given in the ISMB seminar series run jointly by the Department of Biological Sciences at Birkbeck and research departments in neighbouring University College London. The overall title of the programme for Autumn 2011 is "“Proteins of the Future: Mechanism, Evolution and Design” which is closely connected to the content of the PPS course. Other posts may be reports from conferences or summaries of recently published papers in protein structure, protein bioinformatics and allied areas.

Do, if you get a chance, look through some of the earlier posts on the blog to see the kind of topics that we will be discussing. However, don't be discouraged if at this stage of the course you find the science presented there difficult to understand. I can assure you that it will get easier!

And the best of luck for the 2011-12 PPS course and for your studies at Birkbeck! We hope that many of you will go on to complete our MSc in Structural Molecular Biology.

Best wishes,

Dr Clare Sansom

Senior Associate Lecturer, Biological Sciences, Birkbeck and Tutor, Principles of Protein Structure