Diamond Concise Annual Review 2019/20

Macromolecular Crystallography Group M acromolecular crystallography (MX) reveals the shape and arrangement of biological molecules at atomic resolution. The information derived from MX experiments can be complemented by techniques from several other scientific groups at Diamond (including Soft Condensed Matter and Imaging) together with experiments in the researcher’s lab to reveal the broader picture of molecular interactions and their effects. At Diamond seven beamlines (I03, I04, I04-1, I23, I24, VMXi and VMXm), alongside the XChem fragment screening facility, the UK XFEL-hub and the Membrane Protein Facility are dedicated to exploiting the technique of MX for the benefit of the UK structural biology community and researchers across the world. Some of the pioneering studies taking place in the Group this year have included assisting the development of malaria vaccines, innovative research to support the design of new antibiotics, and vital work to find treatments for Covid-19. Developing new vaccines against malaria An international team of researchers has been studying the human antibody response to two potential vaccines against malaria in order to optimise their design. When volunteers are vaccinated, they generate a broad antibody response where some antibodies are effective at neutralising the parasite while others are not.The research team used beamlines I03 and I04 at Diamond to collect data from crystals of the human antibodies bound to their malaria surface protein targets. Their aim was to characterise the structure of the most effective antibodies, to increase understanding of how they work and to design vaccines that generate the most effective antibodies. The research showed that some antibodies directly interfere with the function of malaria surface proteins, preventing them from binding to human red blood cell receptors. This inhibition can also be indirect, probably by stopping the parasite from getting close enough to the red blood cell to allow the interaction to happen. These studies are guiding the design of next-generation vaccine immunogens, where effective neutralising antibodies are produced without generating antibody responses which interfere with their action.These immunogens will be included in the malaria vaccines of the future. Rawlinson TA et al . doi: 10.1038/s41564-019-0462-1 Alanine DGW et al . doi: 10.1016/j.cell.2019.05.025 Understanding how ribosomes work Ribosomes are responsible for the accurate translation of genetic information into proteins in all living cells. Ribosomes and associated molecules, collectively known as the translational apparatus, are the primary target for more than half of current antibiotics. Problems with the translation process are also implicated in a number of human diseases. Ribosomes require metal ions to maintain their structure and function. Until recently, the exact type and location of these metal ions had not been determined. An international team of researchers used beamline I23 to pinpoint hundreds of potassium ions within bacterial ribosomes. This is the only macromolecular crystallography beamline in the world allowing access to long-wavelength X-ray radiation. Using this cutting-edge technique, they were able to demonstrate, for the first time, that potassium ions are not only involved in the overall formation of the structure of ribosomal RNA (rRNA) and ribosomal proteins, but also play an essential role in its function. These results fill a considerable gap in our knowledge and could potentially lead to therapeutic applications. This research could increase the efficiency of drug design and offer targets for the development of new classes of antibiotics. Rozov A et al. doi: 10.1038/s41467-019-10409-4 Designing antivirals to treat Covid-19 There is currently a global race to produce a vaccine against the SARS-CoV-2 virus. However, vaccines in development may not provide long-lasting immunity and will not be suitable for all patients, particularly those whose immune systems are weakened by disease. It is therefore vital to design and investigate new treatments that target the virus itself. Researchers at Diamond are playing a significant role in this effort. In January 2020 Chinese researchers swiftly solved the X-ray structure of a cysteine protease called M pro which is essential to the reproduction of the virus. They shared their findings with teams at Diamond who conducted structural work on the Macromolecular Crystallography (MX) and XChem beamline (I04-1). Speed was vital, as researchers tested thousands of molecules to find promising candidates. Complementary experiments were carried out on other MX beamlines (I03, I04 and I24) to provide additional information. The XChem facility and structural biology labs in the Research Complex at Harwell were essential for rapid sample production and turn-around. This rapid research allowed the team to identify more than 90 compounds worthy of further investigation for development of antivirals for SARS-CoV-2. Although there is no certainty of outcome at this stage, the project highlights Diamond’s role alongside other key centres around the world in producing an antiviral for the treatment of COVID-19. Douangamath A et al . doi: 10.1038/s41467-020-18709-w D I A M O N D L I G H T S O U R C E A N N U A L R E V I E W 2 0 1 9 / 2 0 D I A M O N D L I G H T S O U R C E A N N U A L R E V I E W 2 0 1 9 / 2 0 12 13 Science Highlights