Welcome to new PPS students - and a few more links...

This post is very like those I have written at the beginning of the academic year for the past few years; this is because what I have to say now is also very similar...

I would like to offer a warm welcome to the Principles of Protein Structure blog to all students who have recently started studying Birkbeck's Principles of Protein Structure (PPS) course, and a welcome back to any who have taken a break in studies and intend to complete the course this year. Welcome too if you are thinking that you might want to study with us in the future, or if you are just interested in learning more about a fascinating and fast-moving area of research in molecular biology.

I run this occasional 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. 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 programme for Autumn 2018 has the intriguing title of 'Mischievous Microbes'; its themes of microbiology and infectious disease biology have links to some of the later sections of the course. Other posts may be reports from conferences (such as this one at Imperial College, London in December) or summaries of recently published papers in protein structure and allied areas/

Some earlier posts were written by "guest blogger" Jill Faircloth, who took the MSc in Structural Molecular Biology a few years ago and is now working as a freelance science communicator. She introduces herself in this post written in March 2012, in which she also describes how she found the later part of the PPS course and her thoughts on the two choices available for the second year of the MSc.

Do, if you get a chance, look through some blog posts from earlier years 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!

I also work part-time as a freelance science writer, and sometimes I even have a chance to write about structural biology. You might like to follow a set of blog posts I wrote from the International Union of Crystallography's triennial meeting in Hyderabad, India last summer (posts from 22 August - 6 September). The first entry, featuring a talk by Sir Tom Blundell, a former head of the Department of Crystallography at Birkbeck (now part of the Department of Biological Sciences) is perhaps most relevant to PPS. Sir Tom was involved in solving the structure of HIV protease, target of some of the most successful drugs for AIDS, and he went on to found a drug discovery company, Astex. This year I reported on a meeting much nearer at hand (in Liverpool) and, specifically, on one of the most exciting advances in structural biology by X-ray crystallography for some years: X-ray free electron lasers.

Finally, the best of luck to new students for the 2017-18 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
Tutor, Principles of Protein Structure

The Joy and Pain of Structural Biology

The British Crystallographic Association is, as its name implies, the main organisation supporting crystallograpy and crystallographers in the UK. Theirs is a multi-disciplinary science, and the different needs of the eclectic group of people who call themselves crystallographers are met by the Association's special interest groups: among them, the Biological Structures Group for structural biology. The annual meeting of this group, known as the Winter Meeting, takes place in December, often just a few working days before Christmas. The BSG Winter Meeting has featured on this blog on several occasions: in 2016, it was held at Birkbeck and celebrated the work of one of our distinguished emeritus professors, Steve Wood.

The 2017 meeting, held in the University of Cambridge's famous Cavendish Laboratory, had a rather unusual theme. The organisers asked each of the invited speakers to talk about the ups and downs of their scientific career - the 'joy and pain' of the meeting title - by focusing on one challenging or important piece of work, perhaps described in a single published paper. Not every speaker managed to keep to just one paper, but all the talks gave useful and at times inspiring insights into how structural biology is done.

First of all, however, Malcolm Longair, head of the Cavendish Laboratory from 1997 to 2005 and perhaps the only astrophysicist to address the Biological Structures Group, gave a short history of the university's Physics department that was based there and its links to structural and molecular biology. That early history was quite extraordinary; many of the most important advances in atomic and nuclear physics, including the discoveries of the electron and the neutron and the first controlled nuclear disintegrations, were made there. A lab photo taken in 1932 includes no fewer than nine Nobel laureates.

Crystallography, in those early years, was thought of as part of physics; J.D. Bernal and his group joined the lab in 1931, and the younger Bragg became head of the department in 1938. The rest, as Longair said, was history: seeds of the discipline we now know as structural molecular biology were sown in Bragg's time with Perutz and Kendrew's work on globin structure as well as Watson and Crick's on that of DNA. By the time those studies reached their triumphant conclusion, however, the crystallographers were no longer strictly part of the Cavendish. The 'Unit for Research on the Molecular Structure of Biological Systems’, set up by the Medical Research Council, moved out of the main lab in 1957 into a building known as the 'MRC Hut'. This was the first home of the MRC Laboratory for Molecular Biology (MRC-LMB) at Cambridge with its enduring reputation for excellent structural biology research.

The next speaker, Cambridge University's Tom Blundell, began by describing his early career in 'the Other Place': Dorothy Hodgkin's lab at Oxford, where he had shared some of the glory of the insulin structure. He had considered talking about insulin at this meeting, but, he explained, "Dorothy had had the pain of trying to solve the structure for 30+ years... I had the joy of a paper in Nature!" The story he told instead was his group's own: solving the structures of proteins involved in DNA repair. This was a long story, taking in 15 years' worth of papers in Nature (2002, 2010) and Science (2017) and culminating in the 'great joy' of discovering inhibitors validated against an important protein target for oncology.

DNA damage taking the form of simultaneous breaks in both DNA strands (double-strand breaks) are common but can lead to cell death or cancer. Fortunately, they are easily repaired in healthy cells, mainly through the mechanism of non-homologous end joining (NHEJ). Blundell's group have studied the proteins involved in this complex mechanism for many years. It is a three-stage process, in which the component proteins assemble on the DNA molecule either side of the break; the ends are 'pruned' by adding or removing nucleotides to restore the original sequence and finally, the ends are joined through DNA ligation. One of the proteins involved is a kinase, DNA-PKcs, that exists as a single polypeptide chain of 4128 amino acids. Blundell's group published the structure of this huge molecule in 2010 (PDB 3KGV) and it is still the longest single-chain protein to have been solved by X-ray crystallography. Blundell explained that the chain folds into a flexible, circular 'cradle' like structure that can support the DNA double helix, with the ligation taking place inside. The mechanism requires proteins to work as 'stages, scaffolds and steps' to hold the complex together for repair, and his group has solved structures of many other components including the Ku70-Ku80 heterodimer that recognises and binds to the break, initiating the repair, and a nuclease named Artemis with 'a nice pocket for drug discovery'.

Two talks on structural biology as applied to drug discovery followed. The first was by Pamela Williams from Astex Pharmaceuticals, a company founded by Blundell with Harren Jhoti in 1999 that has just registered its first drug - a kinase inhibitor, Kisqali® (ribociclib) - for clinical use in breast cancer. Williams' talk highlighted another protein family that is just as important in pharmacology as the kinases: cytochromes P450. We have about 50 different P450 subtypes in our livers, and they catalyse reactions that modify drug molecules so they can be more easily removed from our bodies. A handful of these - the subtypes known as 1A9, 2C9, 2C19 and 3D6 - metabolise most prescription drugs. Human (and all eukaryotic) P450s are monotopic membrane proteins with flexible active sites, which allow them to bind a wide variety of substrates but which make the structures hard to solve. Williams' involvement with P450 structural biology began with the first mammalian structure, rabbit cytochrome 2C5, and she joined Astex from California to work on the first human structure, the subtype 2C9. This was published in 2003 (PDB 1OG2); a large number of other human structures have followed, yielding useful insights into drug metabolism.

Ben Bax, who studied for his PhD under Tom Blundell at Birkbeck, has just moved to the University of York after eighteen years at the pharma company GlaxoSmithKline (GSK). His talk described work at GSK to determine the structures of bacterial DNA gyrases. These are members of a large class of enzymes called topoisomerases that catalyse topological transitions in DNA; the gyrase, which catalyses DNA supercoiling, is the target of the widely used quinolone family of antibiotics (e.g. ciprofloxacin). However, quinolone resistance is increasing, mainly through mutations at specific amino acid positions of the target gyrase. GlaxoSmithKline is investing heavily in the development of novel gyrase inhibitors based on oligonucleotides, and Bax' structural biology group has contributed a large number of still unpublished structures of the enzyme with and without inhibitors or DNA bound to this work.

Janet Thornton, emeritus director of the European Bioinformatics Institute, is one of the best known figures in British bioinformatics. Her talk, on what she termed an 'accidental' paper, took the audience back to the basic principles of protein structure. In the late 70s, when she started her career, there were only about fifteen protein structures known but scientists were already examining those structures to determine characteristic patterns. Many of these first structures determined had major inaccuracies, and discovering and correcting these was a major task for early structural biologists. The Ramachandran Plot, now half a century old, was one of the first tools to be developed to gauge the quality of a protein structure, and it is still widely used. Thornton's 'accidental' (and very highly cited) paper described the program PROCHECK, which runs this and other checks on a structure to give a comprehensive assessment of its quality. A PROCHECK record for each structure in the PDB is linked from the database PDBsum.

The final talk provided delegates with a rare opportunity to hear a new Nobel Laureate - in this case, the Laboratory of Molecular Biology's own Richard Henderson - tell the story behind some of his ground-breaking research. Henderson shared the 2017 Chemistry Nobel, for "developing cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution", with Joachim Frank and Jacques Dubochet. He chose to talk about one structure that he had in some senses made his own: that of bacteriorhodopsin, a proton pump found in Archaea that captures light energy as photons and that has many structural and mechanistic similarities with the G-protein coupled receptors, although the exact evolutionary relationship is unclear. Henderson's studies of this important molecule started in the 1970s with structures that were just about detailed enough to show the cylindrical helices. It took him over 15 years'effort with collaborators in Berlin, Berkeley and elsewhere to improve the technology enough to solve the so-called 'phase problem' and obtain an atomic-resolution structure by electron diffraction. The rest, again, is history.

The 2017 ISMB Retreat

The Institute of Structural and Molecular Biology (ISMB) at Birkbeck and UCL holds a conference each summer where all members of the Institute's constituent departments come together to discuss their research. In even years, this takes the form of the ISMB Symposium: two intense days of research talks from ISMB core members and invited research leaders. In odd years, the focus turns to the younger members of the Institute with the ISMB Retreat. This, usually held in Cambridge University's Robinson College, is a two-day residential event featuring plenaries from outside speakers, shorter talks by students and postdocs from the ISMB, an activity designed to get young researchers thinking about science-based careers outside an academic lab, and a poster session. The 2017 retreat, held on June 29 and 30, was the seventh in the series.

There is a full report of this retreat (written by me) with photos on the ISMB website. Do check it out! Here are just a few highlights that are relevant to students of structural biology.

The three keynote speakers were Lori Passmore (MRC Laboratory of Molecular Biology (LMB), Cambridge; Bill Rutherford (Imperial College, London); and Bart Vanhaesebroeck (UCL Cancer Institute). Structural biology was a feature of all three talks, although most prominently in Passmore's. She was recently appointed as a group leader at the LMB, where her group uses high resolution electron microscopy to study the process of poly-adenylation (link to PPS section 8): the addition of the 'poly-A tail' to newly synthesised messenger RNA molecules during the maturation process. Much of the work she discussed has still to be published, apart from a section on techniques development: a physicist in her group, Chris Russo, has worked with her to devise a novel, gold-based substrate for mounting specimens in the electron microscope that eliminates most specimen movement and thus increases resolution.

Bill Rutherford gave an engaging talk, unusually featuring hand-written slides, on the mechanism of action of photosystem II, one of the complex proteins involved in photosynthesis. The evolution of photosynthesis was responsible for the increase in oxygen in the Earth's atmosphere that made multicellular life possible, and Rutherford explained how the increase in oxygen had led to further changes in the structure and mechanism of the photosystem that had the overall effect of decreasing its efficiency. Bart Vanhaesebroeck's lecture, which ended the retreat, described the mechanism of the phosphoinositide-3-kinase family of proteins and their role in cancer. Inhibitors of these kinases (link to PPS section 5) might prove useful anti-cancer drugs, almost certainly as part of combination therapy.

The programme also included nine short talks by students and young postdocs. The excellent quality of these was highlighted by the judges of the best talk, who were unable to come to a consensus judgement. In the end, two equal prizes were given, to Jennifer Booker, who studies the structure of sodium channels (see e.g. this post from September 2016) in Bonnie Wallace's group at Birkbeck, and to Sapir Ofer, for a talk on her PhD studies of the structural and molecular biology of archaeal histones. Proteins in this family are responsible for packing DNA into the chromosomes of eukaryotic cells; bacteria pack DNA using an entirely different mechanism, but the mode of packing in archaea - single-celled organisms that have no nucleus and are defined as prokaryotes but are more closely related to eukaryotes than to bacteria - was unknown until recently.

The retreat always includes an activity to challenge ISMB students and postdocs to think about career opportunities beyond academic research, and this year's proved particularly popular. It was a Dragons' Den style competition in which the younger delegates were split into teams, assigned mentors and given an hour to create a fictitious life science company, develop a bid for funding and present this to a panel of 'dragons'. Three finalists were chosen to battle it out in front of the rest of the delegates. The competitors worked hard and all 'companies' produced ideas that held water to at least some extent, but there could be only one winner. That was a company named TerraNova, which presented an antibody-drug conjugate for primary progressive multiple sclerosis.

ATP synthase: a new drug target for tuberculosis

The London Structural Biology Club (LSBC) is a network for students and researchers working in all aspects of structural molecular biology and based in London and the south-east of England. Once a term, members get together for an afternoon of research talks and discussion followed by refreshments (generally featuring pizza and beer). These meetings are often held at Birkbeck, and we have featured them on the PPS blog before (see this post from 2008 and this one from 2012).

The LSBC meeting for the summer term of 2016 was also held at Birkbeck, and hosted and chaired by Alfonso de Simone, a lecturer in NMR spectroscopy at Imperial College London. One of the four talks was given by Thomas Meier, also from Imperial College. Meier, who has worked at ETH Zurich, Switzerland, and the Max Planck Institute of Biophysics in Frankfurt, Germany, was appointed to a chair of structural biology at Imperial just over a year ago. His research concerns the structure and function of a tiny, complex ‘molecular machine’, ATP synthase (the link is to our page on that enzyme in section 10 of the PPS course). This enzyme is a ‘rotary ATP synthase’, catalysing the conversion of the electrochemical energy of ion transfer across the cell membrane into chemical energy stored in ATP. Meier and his group have solved the complete structure of this multi-subunit enzyme complex using a combination of X-ray crystallography and electron microscopy, and shed light on its role as a target for a novel class of drugs against tuberculosis.

ATP synthase is a highly dynamic enzyme complex, which makes it particularly difficult to study structurally. The complete enzyme comprises two motor sub-complexes; most of one, termed F_o, is embedded in the membrane and the other, F₁, is in the matrix. They are tightly coupled with each other and linked by subunits forming an outer stalk and an inner, central stalk. From a functional point of view, the ATP synthase consists of a rotor and stator part, both sharing subunits from the F₁ and the F_o sectors. The motors are driven either by the proton (or sometimes Na⁺) motive force to form ATP, or in opposite direction by the hydrolysis of ATP to pump ions across the membrane. Similar enzymes are found in the inner membranes of bacteria and mitochondria and in the thylakoid membranes of chloroplasts.

John Walker of the MRC Laboratory of Molecular Biology in Cambridge was awarded a share of the 1997 Nobel Prize in Chemistry for determining the structure of the bovine F1 motor using X-ray crystallography (e.g. PDB 1E79). This subcomplex consists of five different types of subunits; three pairs of similar alpha and beta subunits are arranged alternately around the rotor (gamma / delta / epsilon subunits), which harbours an asymmetric coiled coil domain in the gamma subunit. The nucleotides ADP and ATP can bind to the interfaces between the beta and alpha subunits; the central gamma subunit rotates in 120^o steps, causing conformational changes that in turn change the affinity of the three catalytic sites for the nucleotides. Rotation in one direction, driven by the energy of ion transfer across the membrane, leads to synthesis of ATP from ADP and phosphorus (P_i); rotation in the other direction will hydrolyse ATP back into ADP and P_i, thus releasing the energy required to pump ions.

The membrane-embedded F_o motor consists of the rotor part, a ring of identical c-subunits termed the c-ring and the stator part, a single-chain a-subunit that grants access and release pathways for ions. Each c-ring subunit is a helical hairpin with its N and C termini on the cytoplasmic side; the number of subunits is constant within a species but varies between species, as far as we know today, between 8 and 15 c-subunits. Meier’s group has solved the structures of a number of c-rings from different species of bacteria, helping to elucidate the rotor’s mechanism of action; essentially, protons (or in some cases Na⁺ ions) can reach one of the c-ring subunits by an ion pathway mediated by the stator a-subunit, where they lock to a free ion binding site on the c-ring, rotate with the c-ring for almost a complete 360^o turn to reach the second release pathway that leads to the other side of the membrane. The ion translocation causes rotation of the F_o ring and with it the complete central stalk that protrudes the F₁ headpiece.

Artist's impression of an ATP synthase molecule embedded in a membrane. Image © Laura Preiss, Max Planck Institute of Biophysics, Frankfurt, Germany

Until recently, ATP synthase has not been thought of as a drug target, principally because the structures and mechanisms of the bacterial and human enzymes are so similar. Now, however, it has emerged that it is the target for bedaquiline, the first novel drug to be approved for treating tuberculosis (TB) for over 40 years. And new drugs for TB are needed very badly: in 2015, over 9 million people contracted this disease and about 1.5 million died from it. Tens of thousands of TB cases each year are multidrug resistant (MDR) or even of the extremely drug resistant (XDR) variant for which no other clinically approved antibiotic is available anymore. Bedaquiline, however, is effective against both, MDR- and XDR-TB strains.

Functional analysis has shown that bedaquiline, which is a diarylquinoline, acts by binding to and halting the rotation of the Fo rotor. Meier and his co-workers have now solved the structure of the drug bound to the c-ring from a similar, non-pathogenic bacterial species, Mycobacterium phlei. This structure has nine c-subunits and shares over 80% sequence identity with the M. tuberculosis c-subunit variant (100% match at and around the drug binding surface). The crystal structure (PDB 4V1F; Preiss et al. (2015)) shows the drug occupying the proton-binding site on each of the nine subunits and thus preventing proton transfer. This stalls the rotation of the F_o motor, preventing rotation and thus the synthesis of ATP in F₁. Small differences between the structures of the proton-binding sites account for the exquisite specificity of bedaquiline for the F_o rings of mycobacteria and thus for its efficacy and safety as an anti-tubercular drug.

Meier ended his talk by explaining that TB-causing bacteria will eventually – perhaps sooner rather than later – develop resistance to bedaquiline, just as they have to every previous drug that has entered the clinic. There is therefore a pressing need to develop further drugs that act at the same target, and his group’s structural studies are proving useful in the search for bedaquiline analogues.

The London Structural Biology Club has a public Facebook group, which can be found here.

New protein structures presented at the 2013 BCA Winter Meeting

The work of crystallographers in the UK is supported through the British Cryatallographic Association, which has about 700 members based in academia and industry. It is organised into four groups representing different disciplines within crystallography, including one for structural biologists called, not surprisingly, the Biological Structures Group. Every December, this group organises a one day conference to present some of the most recent developments in structural biology. I have blogged these meetings before, and searching this blog for "winter meeting" will find a few of those posts.

The 2013 meeting was billed as both a "final" event in the centenary year of the Braggs' landmark discoveries and part of the build-up to the International Year of Crystallography, but these were not the only anniversaries highlighted there. 2013 also marked the sixtieth anniversary of the publication of the structure of DNA. The 2013 Winter Meeting was held in King's College London, which played a very important part in that discovery: Maurice Wilkins and Rosalind Franklin, who obtained the X-ray diffraction patterns that led to the discovery of the double helix, were based there. (Wilkins shared the Nobel Prize for this discovery with Watson and Crick; Franklin died in 1958, four years before that prize was awarded.) And the first precise physical model of the double helix is still on display in the college.

Maurice Wilkins' original DNA model

The first researcher to speak at the meeting was Birkbeck's own Professor Bonnie Wallace. Her work on the structures of voltage gated sodium channels has been described on this blog before, most recently in April 2013. These proteins are responsible for the transport of ions in and out of cells, an essential signalling mechanism in all multi-cellular organisms. Their structures, however, are among the most intractable of all membrane proteins (PPS section 11, to be released in May, covers this fast moving field). Wallace has used a combination of X-ray crystallography, spectroscopy and molecular dynamics to explore the structure and mechanism of sodium channels in bacteria. The bacterial sodium channel is simpler than the mammalian equivalent, consisting of a tetramer in which helices from each monomer line the pore. The Wallace group's most recent strucure (PDB 3ZJZ) shows the position of the C-terminal domain of these channels for the first time. This domain consists of a coiled coil formed by one helix from each monomer that is linked to the rest of the protein by a flexible region. Moving the coiled coil up and down causes a conformational change that allows the channel to open and close.

The technique of rational or structure-based drug design, which involve modelling the interactions between a library of potential ligands and a protein binding site, has proved particularly successful in the design of anti-viral drugs. Several inhibitors of HIV protease and of influenza virus neuraminidase that were designed in this way have become very successful drugs. David Stuart from the University of Oxford and the Diamond synchrotron gave a talk illustrating how structure-based in silico techniques are now being applied to design drugs against another virus family: the Picornaviruses. Members of this large family are responsible for a diverse range of diseases, ranging in humans from polio to the common cold. The foot-and-mouth virus, which affects livestock and which devastated parts of the UK countryside in 2001, is also a member of this family.

One of the viruses studied in Stuart's goup is a human picornavirus that causes similar symptoms to the foot-and-mouth virus and that represents a serious threat to public health in East Asia. The disease is known as hand foot and mouth virus, and the virus as CAV16: like all picornaviruses, it consiss of a single strand of RNA enclosed within an icosahedral (20-sided) protein capsid. The intact virus particles are very fragile and diffraction patterns must be captured before the particles disintegrate in the X-ray beam. Stuart and his Chinese collaborators have used one of the microfocus beamlines at Diamond to take snapshots of the virus structure at several points during its life cycle. One of these is of an "uncoating intermediate" that shows one of the viral proteins (VP1) emerging from the capsid so that it can be embedded in the membrane of a host cell Ren et al., 2013). Stuart and his co-workers are now designing compounds to bind to these intermediate structures and prevent the virus from entering its human host cells.

All cells, whether prokaryotic or eukaryotic, contain long molecules of DNA that must be packaged in order to fit into the confined space available. Fortunately for developers of anti-bacterial drugs (and users of antibiotics) bacterial cells package DNA using a different mechanism from mammalian ones. In bacteria, enzymes called topoisomerases bind to, cut and re-join double-stranded DNA so that it can be unwound or untangled ahead of replication. Ivan Laponogov, a postdoctoral research assistant at King's College, described recent work in his group on the structure of one of these enzymes. Bacterial topoisomerase II ia a target for an important class of antibiotics, the fluoroquinolones, but resistance to these drugs is increasing.

These enzymes are powered by ATP and act as "clamps", capturing one double-helical strand of DNA and passing it through a break in another to remove supercoils and knots in the nucleic acid structure. The structure presented at this meeting was the first of a complete topoisomerase dimer bound to DNA in the "open clamp" position. This structure was solved with and without a fluoroquinolone drug (levofloxacin) bound. The structure with drug bound showed that molecule intercalating between DNA bases at the point where the nucleic acid would be cleaved, preventing that cleavage. The structure without the drug showed the DNA in a different position; the position of a functionally important magnesium ion also changed between the structures.

Many essential cellular processes involve a post-translational modification in which poly-(ADP ribose) or PAR is added to amino acid side chains, and the processing of this molecule involves a wide variety of enzymes. Inhibitors of one of these, poly-(ATP ribose) polymerase or PARP, have recently been developed as drugs against cancer. David Leys from the University of Manchester described his work on the structure of another enzyme in the PAR life cycle: poly-ADP-ribose glycohydrolase (PARG), which catalyses the removal of PAR from proteins.

Mammalian PARG enzymes have three domains, a N-terminal regulatory region and two C-terminal domains forming the catalytic region; the equivalent bacterial enzymes lack the N-terminus. Leys and his groups first solved structures of a bacterial PARG bound to ADP-ribose (PDB 3SIG) and to a known inhibitor with a similar structure. They found that a C-terminal helix in the protein was clamped around the terminal ribose of PAR, enabling the release of a single ADP-ribose from the polymer. This basic mechanism is similar in the mammalian enzyme. More recently, the Leys group has solved the structure of PARG bound to an intact PAR substrate (PDB 4L2H); modelling studies based on this structure suggest that the enzyme acts predominantly as an exo-glycohydrolase, that is, it catalyses the removal of one residue at the end of the polymer chain. Understanding the structure and mechanism of these enzymes should enable us to develop small-molecule inhibitors of PARG, and these may one day rival the PARP inhibitors as anti-cancer drugs.

A hundred years on from the "invention" of crystallography and sixty years on from the structure of DNA, these elegant, fascinating and complex structures presented at one meeting give a snapshot of recent progress in structural biology. Furthermore, each of these structures has already provided insights into human disease that may yet lead to the development of useful drugs.