SARS-CoV-2 is a coronavirus similar to the SARS and MERS viruses that caused epidemics in 2002 and 2012, respectively. Understanding the biochemical and structural makeup of the virus is absolutely crucial for the development of drugs and tremendously helpful for the design of vaccines.
The structure of the main protease of SARS-CoV-2 in complex1 with a coronavirus covalent inhibitor (N3) has been determined by X-ray crystallography by Zihe Rao, Haitao Yang and colleagues at ShanghaiTech University, less than a month after the virus sequences were made available. The data were collected with an EIGER X 16M detector at beamline 17U1 of the Shanghai Synchrotron Radiation Facility in China (Fig 1).
Based on the structure, the Shanghai team virtually screened a large number of existing drugs and biologically active natural products to assess their potential as therapeutics against SARS-CoV-2. They selected 30 candidates that are now being further characterised using the X-Chem facility at Diamond Light Source to accelerate ligand-screening efforts.
Structural biology is indeed moving quickly. Over the last few days, four structures of various aspects of the CoV-2 spike protein were solved by crystallography and electron cryo-microscopy (cryo-EM) by groups from the United States and China. The trimeric spike protein (Fig 2A) protrudes from the surface of the viral capsid to give it the appearance of a crown, which gave the family of viruses its name. This protein is a key target for potential vaccines, therapeutic antibodies, and diagnostics.
The receptor-binding domain (RBD) of the spike protein binds strongly to angiotensin-converting enzyme 2 (ACE2, Figure 2B), the receptor that invites SARS into human cells. It does not bind to several tested antibodies active against SARS, but the structure suggests where and how antibodies might bind. The high-resolution crystal structure of the CoV-2 spike protein RBD bound to the peptidase domain of ACE2 (Figure 2C), determined from data collected with an EIGER X 16 at beamline 17U1 of the Shanghai synchrotron, shows a binding mode nearly identical to that of the SARS RBD to ACE2.
This content was developed in collaboration with Dectris whose detectors have been used in all the MX experiments at Diamond.
Diamond Light Source is the UK's national synchrotron science facility, located at the Harwell Science and Innovation Campus in Oxfordshire.
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