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

View ORCID ProfileTomer Meirson, David Bomze, Gal Markel
doi: https://doi.org/10.1101/2020.05.24.113175
Tomer Meirson
aAzrieli Faculty of Medicine, Bar-Ilan University, Israel
bElla Lemelbaum Institute for Immuno-oncology, Sheba Medical Center, Ramat-Gan 526260, Israel
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  • For correspondence: tomermrsn@gmail.com gal.markel@sheba.health.gov.il
David Bomze
cSackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
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Gal Markel
bElla Lemelbaum Institute for Immuno-oncology, Sheba Medical Center, Ramat-Gan 526260, Israel
dDepartment of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel
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  • For correspondence: tomermrsn@gmail.com gal.markel@sheba.health.gov.il
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Abstract

Motivation The recent emergence of the novel SARS-coronavirus 2 (SARS-CoV-2) and its international spread pose a global health emergency. The viral spike (S) glycoprotein binds the receptor (angiotensin-converting enzyme 2) ACE2 and promotes SARS-CoV-2 entry into host cells. The trimeric S protein binds the receptor using the distal receptor-binding domain (RBD) causing conformational changes in S protein that allow priming by host cell proteases. Unravelling the dynamic structural features used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal novel therapeutic targets. Using structures determined by X-ray crystallography and cryo-EM, we performed structural analysis and atomic comparisons of the different conformational states adopted by the SARS-CoV-2-RBD.

Results Here, we determined the key structural components induced by the receptor and characterized their intramolecular interactions. We 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. We 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. This 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 us 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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 24, 2020.
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Structural basis of SARS-CoV-2 spike protein induced by ACE2
Tomer Meirson, David Bomze, Gal Markel
bioRxiv 2020.05.24.113175; doi: https://doi.org/10.1101/2020.05.24.113175
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Structural basis of SARS-CoV-2 spike protein induced by ACE2
Tomer Meirson, David Bomze, Gal Markel
bioRxiv 2020.05.24.113175; doi: https://doi.org/10.1101/2020.05.24.113175

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