Structural plasticity of SARS-CoV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography

Daniel W. Kneller; Gwyndalyn Phillips; Hugh M. O’Neill; Robert Jedrzejczak; Lucy Stols; Paul Langan; Andrzej Joachimiak; Leighton Coates; Andrey Kovalevsky

doi:10.1038/s41467-020-16954-7

Structural plasticity of SARS-CoV-2 3CL M^pro active site cavity revealed by room temperature X-ray crystallography

Daniel W. Kneller, Gwyndalyn Phillips, Hugh M. O’Neill, Robert Jedrzejczak, Lucy Stols, Paul Langan, Andrzej Joachimiak, Leighton Coates, Andrey Kovalevsky

Research output: Contribution to journal › Article › peer-review

324 Scopus citations

Abstract

The COVID-19 disease caused by the SARS-CoV-2 coronavirus has become a pandemic health crisis. An attractive target for antiviral inhibitors is the main protease 3CL M^pro due to its essential role in processing the polyproteins translated from viral RNA. Here we report the room temperature X-ray structure of unliganded SARS-CoV-2 3CL M^pro, revealing the ligand-free structure of the active site and the conformation of the catalytic site cavity at near-physiological temperature. Comparison with previously reported low-temperature ligand-free and inhibitor-bound structures suggest that the room temperature structure may provide more relevant information at physiological temperatures for aiding in molecular docking studies.

Original language	English
Article number	3202
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16954-7
State	Published - Dec 1 2020

Funding

This work was supported by the Laboratory Directed Research and Development Program at Oak Ridge National Laboratory (ORNL). Research at ORNL’s Spallation Neutron Source and HFIR was sponsored by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy. The Office of Biological and Environmental Research supported research at ORNL’s Center for Structural Molecular Biology (CSMB), using facilities supported by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy. Funding for this project was provided in part by federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract HHSN272201700060C. Crystallization screening was supported through NSF grant 2029943. We thank Swati Pant, Kevin Weiss, Yichong Fan, Qiu Zhang of ORNL for their help with the plasmid preparation and initial protein expression.

Funders	Funder number
Office of Basic Energy Sciences
Office of Biological and Environmental Research
Scientific User Facilities Division
National Science Foundation	2029943
National Institutes of Health
U.S. Department of Energy
U.S. Department of Health and Human Services	HHSN272201700060C
National Institute of Allergy and Infectious Diseases
Basic Energy Sciences
Oak Ridge National Laboratory

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-020-16954-7

Cite this

@article{feeec5f19132427ab2196364c96f08ef,

title = "Structural plasticity of SARS-CoV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography",

abstract = "The COVID-19 disease caused by the SARS-CoV-2 coronavirus has become a pandemic health crisis. An attractive target for antiviral inhibitors is the main protease 3CL Mpro due to its essential role in processing the polyproteins translated from viral RNA. Here we report the room temperature X-ray structure of unliganded SARS-CoV-2 3CL Mpro, revealing the ligand-free structure of the active site and the conformation of the catalytic site cavity at near-physiological temperature. Comparison with previously reported low-temperature ligand-free and inhibitor-bound structures suggest that the room temperature structure may provide more relevant information at physiological temperatures for aiding in molecular docking studies.",

author = "Kneller, {Daniel W.} and Gwyndalyn Phillips and O{\textquoteright}Neill, {Hugh M.} and Robert Jedrzejczak and Lucy Stols and Paul Langan and Andrzej Joachimiak and Leighton Coates and Andrey Kovalevsky",

note = "Publisher Copyright: {\textcopyright} 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-16954-7",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - Structural plasticity of SARS-CoV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography

AU - Kneller, Daniel W.

AU - Phillips, Gwyndalyn

AU - O’Neill, Hugh M.

AU - Jedrzejczak, Robert

AU - Stols, Lucy

AU - Langan, Paul

AU - Joachimiak, Andrzej

AU - Coates, Leighton

AU - Kovalevsky, Andrey

PY - 2020/12/1

Y1 - 2020/12/1

N2 - The COVID-19 disease caused by the SARS-CoV-2 coronavirus has become a pandemic health crisis. An attractive target for antiviral inhibitors is the main protease 3CL Mpro due to its essential role in processing the polyproteins translated from viral RNA. Here we report the room temperature X-ray structure of unliganded SARS-CoV-2 3CL Mpro, revealing the ligand-free structure of the active site and the conformation of the catalytic site cavity at near-physiological temperature. Comparison with previously reported low-temperature ligand-free and inhibitor-bound structures suggest that the room temperature structure may provide more relevant information at physiological temperatures for aiding in molecular docking studies.

AB - The COVID-19 disease caused by the SARS-CoV-2 coronavirus has become a pandemic health crisis. An attractive target for antiviral inhibitors is the main protease 3CL Mpro due to its essential role in processing the polyproteins translated from viral RNA. Here we report the room temperature X-ray structure of unliganded SARS-CoV-2 3CL Mpro, revealing the ligand-free structure of the active site and the conformation of the catalytic site cavity at near-physiological temperature. Comparison with previously reported low-temperature ligand-free and inhibitor-bound structures suggest that the room temperature structure may provide more relevant information at physiological temperatures for aiding in molecular docking studies.

UR - http://www.scopus.com/inward/record.url?scp=85086902301&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-16954-7

DO - 10.1038/s41467-020-16954-7

M3 - Article

C2 - 32581217

AN - SCOPUS:85086902301

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3202

ER -