Open AccessAn extended conformation of SARS-CoV-2 main protease reveals allosteric targets
Author(s) -
Zengchao Sun,
Lucy Wang,
Xiyang Li,
Chengpeng Fan,
Jianfeng Xu,
Zhenzhong Shi,
Huarui Qiao,
Zhongyun Lan,
Xin Zhang,
Lingyun Li,
Xin Zhou,
Yong Geng
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2120913119
Subject(s) - allosteric regulation , chemistry , protease , coronavirus , monomer , covid-19 , protein structure , stereochemistry , structural biology , biophysics , computational biology , biochemistry , enzyme , biology , polymer , medicine , disease , organic chemistry , pathology , infectious disease (medical specialty)
Significance The 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 .