Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoprotein
At the end of 2019, a new highly virulent coronavirus known under the name SARS-CoV-2 emerged as a human pathogen. One key feature of SARS-CoV-2 is the presence of an enigmatic insertion in the spike glycoprotein gene representing a novel multibasic S1/S2 protease cleavage site. The proteolytic clea...
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doaj-33cffc7140784d6295aae0a7c5b46d8b2020-12-19T05:10:58ZengElsevierJournal of Structural Biology: X2590-15242020-01-014100038Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoproteinThomas Lemmin0David Kalbermatter1Daniel Harder2Philippe Plattet3Dimitrios Fotiadis4DS3Lab, System Group, Department of Computer Sciences, ETH Zurich, CH-8092 Zürich, Switzerland; Trkola Group, Institute for Virology, University of Zurich, CH-8057 Zürich, Switzerland; Corresponding authors at: S3Lab, System Group, Department of Computer Sciences, ETH Zurich, CH-8092 Zürich, Switzerland (T. Lemmin) and Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012 Bern, Switzerland (D. Fotiadis).Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, CH-3012 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, CH-3012 Bern, SwitzerlandDivision of Experimental and Clinical Research, Vetsuisse Faculty, University of Bern, CH-3012 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, CH-3012 Bern, Switzerland; Corresponding authors at: S3Lab, System Group, Department of Computer Sciences, ETH Zurich, CH-8092 Zürich, Switzerland (T. Lemmin) and Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012 Bern, Switzerland (D. Fotiadis).At the end of 2019, a new highly virulent coronavirus known under the name SARS-CoV-2 emerged as a human pathogen. One key feature of SARS-CoV-2 is the presence of an enigmatic insertion in the spike glycoprotein gene representing a novel multibasic S1/S2 protease cleavage site. The proteolytic cleavage of the spike at this site is essential for viral entry into host cells. However, it has been systematically abrogated in structural studies in order to stabilize the spike in the prefusion state. In this study, multi-microsecond molecular dynamics simulations and ab initio modeling were leveraged to gain insights into the structures and dynamics of the loop containing the S1/S2 protease cleavage site. They unveiled distinct conformations, formations of short helices and interactions of the loop with neighboring glycans that could potentially regulate the accessibility of the cleavage site to proteases and its processing. In most conformations, this loop protrudes from the spike, thus representing an attractive SARS-CoV-2 specific therapeutic target.http://www.sciencedirect.com/science/article/pii/S2590152420300209Ab initio modellingCoronavirusFurin cleavage siteMolecular dynamics simulationSARS-CoV-2Spike glycoprotein |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Thomas Lemmin David Kalbermatter Daniel Harder Philippe Plattet Dimitrios Fotiadis |
spellingShingle |
Thomas Lemmin David Kalbermatter Daniel Harder Philippe Plattet Dimitrios Fotiadis Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoprotein Journal of Structural Biology: X Ab initio modelling Coronavirus Furin cleavage site Molecular dynamics simulation SARS-CoV-2 Spike glycoprotein |
author_facet |
Thomas Lemmin David Kalbermatter Daniel Harder Philippe Plattet Dimitrios Fotiadis |
author_sort |
Thomas Lemmin |
title |
Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoprotein |
title_short |
Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoprotein |
title_full |
Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoprotein |
title_fullStr |
Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoprotein |
title_full_unstemmed |
Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoprotein |
title_sort |
structures and dynamics of the novel s1/s2 protease cleavage site loop of the sars-cov-2 spike glycoprotein |
publisher |
Elsevier |
series |
Journal of Structural Biology: X |
issn |
2590-1524 |
publishDate |
2020-01-01 |
description |
At the end of 2019, a new highly virulent coronavirus known under the name SARS-CoV-2 emerged as a human pathogen. One key feature of SARS-CoV-2 is the presence of an enigmatic insertion in the spike glycoprotein gene representing a novel multibasic S1/S2 protease cleavage site. The proteolytic cleavage of the spike at this site is essential for viral entry into host cells. However, it has been systematically abrogated in structural studies in order to stabilize the spike in the prefusion state. In this study, multi-microsecond molecular dynamics simulations and ab initio modeling were leveraged to gain insights into the structures and dynamics of the loop containing the S1/S2 protease cleavage site. They unveiled distinct conformations, formations of short helices and interactions of the loop with neighboring glycans that could potentially regulate the accessibility of the cleavage site to proteases and its processing. In most conformations, this loop protrudes from the spike, thus representing an attractive SARS-CoV-2 specific therapeutic target. |
topic |
Ab initio modelling Coronavirus Furin cleavage site Molecular dynamics simulation SARS-CoV-2 Spike glycoprotein |
url |
http://www.sciencedirect.com/science/article/pii/S2590152420300209 |
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