8 Jun 2020

Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody

The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in an unprecedented public health crisis. There are no approved vaccines or therapeutics for treating COVID-19. Here we reported a humanized monoclonal antibody, H014, efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nM level by engaging the S receptor binding domain (RBD). Importantly, H014 administration reduced SARS-CoV-2 replication and prevented pulmonary pathology in hACE2 mouse model. Cryo-EM characterization of the SARS- CoV-2 Strimer in complex with the H014 Fab fragment unveiled a novel conformational epitope, which is only accessible when the RBD is in open conformation. Biochemical, cellular, virological and structural studies demonstrated that H014 prevents attachment of SARS-CoV-2 to its host cell receptors. Epitope analysis of available neutralizing antibodies against SARS-CoV and SARS-CoV-2 uncover broad cross-protective epitopes. Results of Liangzhi Xi, Youchun Wang, Zihe Rao, Cheng-Feng Qi and Xiangxi Wang highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19.

28 May 2020

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, Nir London, Frank von Delft, Martin A. Walsh et.al.  performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. The crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments was progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

27 May 2020

Controlling the SARS-CoV-2 Spike Glycoprotein Conformation

The coronavirus (CoV) viral host cell fusion spike (S) protein is the primary immunogenic target for virus neutralization and the current focus of many vaccine design efforts. The highly flexible S-protein, with its mobile domains, presents a moving target to the immune system. In the bioRcin paper, to better understand S-protein mobility, a structure-based vector analysis of available β-CoV S-protein structures was implemented.  Rory Henderson, Priyamvada Acharya et.al. from Duke Human Vaccine Institute, Durham, USA found that despite overall similarity in domain organization, different β-CoV strains display distinct S-protein configurations. Based on this analysis, we developed two soluble ectodomain constructs in which the highly immunogenic and mobile receptor binding domain (RBD) is locked in either the all-RBDs ‘down’ position or is induced to display a previously unobserved in SARS-CoV-2 2-RBDs ‘up’ configuration. These results demonstrate that the conformation of the S-protein can be controlled via rational design and provide a framework for the development of engineered coronavirus spike proteins for vaccine applications.

5 Aug 2019

Frontiers in Cryo Electron Microscopy of Complex Macromolecular Assemblies

In this publication Sriram Subramaniam et. al. report on structural studies of G protein–coupled receptors, spliceosomes, and fibrillar specimens and illustrate the progress made by advanced cryo-EM methods.

1 Aug 2019

The evolution of solution state NMR pulse sequences through the ‘eyes’ of triple-resonance spectroscopy

Lewis Kay in The evolution of solution state NMR pulse sequences through the ‘eyes’ of triple-resonance spectroscopy highlights how pulse sequence ‘engineering’ has evolved during past decades with the focus on liquid state NMR applications.

Principles for Integrative Structural Biology Studies

Guru of integrative structural biology computation Andrej Sali and Michale P. Rout summarize in the recent Cell Primer Principles for Integrative Structural Biology Studies.

Visualization of biological macromolecules at near-atomic resolution: cryo-electron microscopy comes of age

The topical review by Alok K. Mitra recapitulates developments and transformational advances of cryo-EM technology.

16 Jul 2019

The expanding toolkit for structural biology: synchrotrons, X-ray lasers and cryo-EM

Samar Hasnain et. al. describe the steadily-expanding methodologies for atomic resolution studies in The expanding toolkit for structural biology: synchrotrons, X-ray lasers and cryo-EM. Of note is the following statistics: Despite the wealth of structures in the Protein Data Bank, a closer examination reveals that 89% of the structures, i.e. 126 994, are of proteins or complexes with a molecular weight of less than 160 kDa. Furthermore, only 4% of the deposited structures have a molecular weight in excess of 300 kDa.