An extended conformation of SARS-CoV-2 main protease reveals allosteric targets

Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2120913119. doi: 10.1073/pnas.2120913119. Epub 2022 Mar 24.

Abstract

SignificanceThe coronavirus main protease (Mpro) is required for viral replication. Here, we obtained the extended conformation of the native monomer of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mpro by trapping it with nanobodies and found that the catalytic domain and the helix domain dissociate, revealing allosteric targets. Another monomeric state is termed compact conformation and is similar to one protomer of the dimeric form. We designed a Nanoluc Binary Techonology (NanoBiT)-based high-throughput allosteric inhibitor assay based on structural conformational change. Our results provide insight into the maturation, dimerization, and catalysis of the coronavirus Mpro and pave a way to develop an anticoronaviral drug through targeting the maturation process to inhibit the autocleavage of Mpro.

Keywords: Mpro compact conformation; Mpro extended conformation; SARS-CoV-2 main protease; nanobody.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Antiviral Agents* / chemistry
  • Antiviral Agents* / pharmacology
  • COVID-19* / enzymology
  • Coronavirus 3C Proteases* / antagonists & inhibitors
  • Coronavirus 3C Proteases* / chemistry
  • Humans
  • Luciferases
  • Protease Inhibitors* / chemistry
  • Protease Inhibitors* / pharmacology
  • Protein Conformation
  • Protein Multimerization
  • SARS-CoV-2*

Substances

  • Antiviral Agents
  • Protease Inhibitors
  • Luciferases
  • nanoluc
  • 3C-like proteinase, SARS-CoV-2
  • Coronavirus 3C Proteases