Proc Natl Acad Sci U S A . An extended conformation of SARS-CoV-2 main protease reveals allosteric targets

[tetano]

Proc Natl Acad Sci U S A


. 2022 Apr 12;119(15):e2120913119.
doi: 10.1073/pnas.2120913119. Epub 2022 Mar 24.
An extended conformation of SARS-CoV-2 main protease reveals allosteric targets


Zengchao Sun[SUP] 1 2 [/SUP], Lu Wang[SUP] 1 [/SUP], Xiyang Li[SUP] 1 [/SUP], Chengpeng Fan[SUP] 3 [/SUP], Jianfeng Xu[SUP] 2 [/SUP], Zhenzhong Shi[SUP] 2 [/SUP], Huarui Qiao[SUP] 2 [/SUP], Zhongyun Lan[SUP] 2 [/SUP], Xin Zhang[SUP] 2 [/SUP], Lingyun Li[SUP] 1 [/SUP], Xin Zhou[SUP] 2 [/SUP], Yong Geng[SUP] 1 4 [/SUP]



Affiliations

• PMID: 35324337
• DOI: 10.1073/pnas.2120913119

Abstract

SignificanceThe coronavirus main protease (M[SUP]pro[/SUP]) 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) M[SUP]pro[/SUP] 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 M[SUP]pro[/SUP] and pave a way to develop an anticoronaviral drug through targeting the maturation process to inhibit the autocleavage of M[SUP]pro[/SUP].

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