The S2 Pocket Governs the Genus-Specific Substrate Selectivity of Coronavirus 3C-Like Protease.

ABSTRACT: Coronavirus 3C-like protease (CoV 3CL^pro) is essential for viral replication, providing an attractive target for monitoring the evolution of CoV and developing anti-CoV drugs. Here, the substrate-binding modes of 3CL^pros from four CoV genera are analyzed and found that the S2 pocket in 3CL^pro is highly conserved within each genus but differs between genera. Functionally, the S2 pocket, in conjunction with S4 and S1' pockets, governs the genus-specific substrate selectivity of 3CL^pro. Resurrected ancestral 3CL^pros from four CoV genera validate the genus-specific divergence of S2 pocket. Drawing upon the genus-specific S2 pocket as evolutionary marker, eight newly identified 3CL^pros uncover the ancestral state of modern 3CL

SUBMITTER: Zhou J 

PROVIDER: S-EPMC11600255 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature