26 May 2020

Distinct conformational states of SARS-CoV-2 spike protein

The ongoing SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic has created urgent needs for intervention strategies to control the crisis. The spike (S) protein of the virus forms a trimer and catalyzes fusion between viral and target cell membranes - the first key step of viral infection. Bing Chen et. al. report two cryo-EM structures, both derived from a single preparation of the full-length S protein, representing the prefusion (3.1Å resolution) and postfusion (3.3Å resolution) conformations, respectively. The spontaneous structural transition to the postfusion state under mild conditions is independent of target cells. The prefusion trimer forms a tightly packed structure with three receptor-binding domains clamped down by a segment adjacent to the fusion peptide, significantly different from recently published structures of a stabilized S ectodomain trimer. The postfusion conformation is a rigid tower-like trimer, but decorated by N-linked glycans along its long axis with almost even spacing, suggesting possible involvement in a mechanism protecting the virus from host immune responses and harsh external conditions. These findings advance understanding of how SARS-CoV-2 enters a host cell and may guide development of vaccines and therapeutics.

25 May 2020

Structural basis of SARS-CoV-2 spike protein induced by ACE2

In the preliminary paper, published in bioRxiv, Gal Marker et al. from the Institute for Immuno-oncology, Sheba Medical Center, Israel, determined the key structural changes of spike protein components induced by the receptor and characterized their intramolecular interactions. They show that κ-helix (also known as polyproline II) is a predominant structure in the binding interface and in facilitating the conversion to the active form of the S protein. They demonstrate a series of conversions between switch-like κ-helix and β-strand, and conformational variations in a set of short α-helices which affect the proximal hinge region. These conformational changes lead to an alternating pattern in conserved disulfide bond configurations positioned at the hinge, indicating a possible disulfide exchange, an important allosteric switch implicated in viral entry of various viruses, including HIV and murine coronavirus. The structural information presented herein enables them to inspect and understand the important dynamic features of SARS-CoV-2-RBD and propose a novel potential therapeutic strategy to block viral entry. Overall, this study provides guidance for the design and optimization of structure-based intervention strategies that target SARS-CoV-2.

18 May 2020

Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by Remdesivir

The pandemic of Corona Virus Disease 2019 (COVID-19) caused by SARS-CoV-2 has become a global crisis. The replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp), a target of the antiviral drug, Remdesivir. In the Science paper (published May 1, 2020) Yechun Xu, Shuyang Zhang, Yan Zhang, and H. Eric Xu report the cryo-EM structure of the SARS-CoV-2 RdRp either in the apo form at 2.8 Å resolution or in complex with a 50-base template-primer RNA and Remdesivir at 2.5 Å resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp where Remdesivir is covalently incorporated into the primer strand at the first replicated base pair and terminates chain elongation. The obtained structures provide critical insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.

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.