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

Journal Article · · Nature Communications
 [1];  [1];  [1];  [2];  [3];  [1];  [4];  [1];  [1]
  1. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  2. Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
  3. Univ. of Chicago, IL (United States)
  4. Argonne National Lab. (ANL), Argonne, IL (United States); Univ. of Chicago, IL (United States)
+ Show Author Affiliations
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.
Research Organization:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); National Science Foundation (NSF)
Grant/Contract Number:
AC05-00OR22725; AC02-06CH11357
OSTI ID:
1649205
Alternate ID(s):
OSTI ID: 1798833
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

References (41)

Viral cysteine proteinases journal December 1996
Activation and maturation of SARS-CoV main protease journal April 2011
Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes journal March 1977
A deliberate approach to screening for initial crystallization conditions of biological macromolecules journal April 2003
Characterization of SARS main protease and inhibitor assay using a fluorogenic substrate journal June 2004
Screening of electrophilic compounds yields an aziridinyl peptide as new active-site directed SARS-CoV main protease inhibitor journal December 2005
Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: Design, synthesis, biological evaluation, and docking studies journal October 2013
Discovery of unsymmetrical aromatic disulfides as novel inhibitors of SARS-CoV main protease: Chemical synthesis, biological evaluation, molecular docking and 3D-QSAR study journal September 2017
GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers journal September 2015
An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy journal February 2016
Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases journal March 2020
3C-like Proteinase from SARS Coronavirus Catalyzes Substrate Hydrolysis by a General Base Mechanism † journal April 2004
Steady-State and Pre-Steady-State Kinetic Evaluation of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL pro Cysteine Protease:  Development of an Ion-Pair Model for Catalysis journal February 2008
Design and Synthesis of Peptidomimetic Severe Acute Respiratory Syndrome Chymotrypsin-like Protease Inhibitors journal November 2005
Discovery, Synthesis, And Structure-Based Optimization of a Series of N -( tert -Butyl)-2-( N -arylamido)-2-(pyridin-3-yl) Acetamides (ML188) as Potent Noncovalent Small Molecule Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease journal January 2013
CHARMM36m: an improved force field for folded and intrinsically disordered proteins journal November 2016
The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2 journal March 2020
A new coronavirus associated with human respiratory disease in China journal February 2020
A pneumonia outbreak associated with a new coronavirus of probable bat origin journal February 2020
Author Correction: A new coronavirus associated with human respiratory disease in China journal April 2020
Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors journal April 2020
Canonical sampling through velocity rescaling journal January 2007
Polymorphic transitions in single crystals: A new molecular dynamics method journal December 1981
Comparison of simple potential functions for simulating liquid water journal July 1983
Molecular dynamics with coupling to an external bath journal October 1984
SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity journal October 2016
Biosynthesis, Purification, and Substrate Specificity of Severe Acute Respiratory Syndrome Coronavirus 3C-like Proteinase journal October 2003
Critical Assessment of Important Regions in the Subunit Association and Catalytic Action of the Severe Acute Respiratory Syndrome Coronavirus Main Protease journal April 2005
A molecular dynamics method for simulations in the canonical ensemble journal June 1984
Inhibition of SARS-CoV 3CL protease by flavonoids journal November 2019
Essential covalent linkage between the chymotrypsin-like domain and the extra domain of the SARS-CoV main protease journal August 2010
Canonical dynamics: Equilibrium phase-space distributions journal March 1985
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Features and development of Coot journal March 2010
Overview of the CCP 4 suite and current developments journal March 2011
How good are my data and what is the resolution? journal June 2013
From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design journal August 2014
Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors journal March 2020
Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease journal April 2020
Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV journal February 2020

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
hydrolases
target validation
x-ray crystallography