Functional dynamics of SARS-CoV-2 3C-like protease as a member of clan PA

Akinori Kidera; Kei Moritsugu; Toru Ekimoto; Mitsunori Ikeguchi

doi:10.1007/s12551-022-01020-x

Functional dynamics of SARS-CoV-2 3C-like protease as a member of clan PA

Biophys Rev. 2022 Dec 2;14(6):1473-1485. doi: 10.1007/s12551-022-01020-x. eCollection 2022 Dec.

Authors

Akinori Kidera¹, Kei Moritsugu^{1

2}, Toru Ekimoto¹, Mitsunori Ikeguchi¹

Affiliations

¹ Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-Cho, Tsurumi, Yokohama 230-0045 Japan.
² Present Address: Graduate School of Science, Osaka Metropolitan University, 1-1 Gakuen-Cho, Nakaku, Sakai, Osaka 599-8570 Japan.

Abstract

SARS-CoV-2 3C-like protease (3CL^pro), a potential therapeutic target for COVID-19, consists of a chymotrypsin fold and a C-terminal α-helical domain (domain III), the latter of which mediates dimerization required for catalytic activation. To gain further understanding of the functional dynamics of SARS-CoV-2 3CL^pro, this review extends the scope to the comparative study of many crystal structures of proteases having the chymotrypsin fold (clan PA of the MEROPS database). First, the close correspondence between the zymogen-enzyme transformation in chymotrypsin and the allosteric dimerization activation in SARS-CoV-2 3CL^pro is illustrated. Then, it is shown that the 3C-like proteases of family Coronaviridae (the protease family C30), which are closely related to SARS-CoV-2 3CL^pro, have the same homodimeric structure and common activation mechanism via domain III mediated dimerization. The survey extended to order Nidovirales reveals that all 3C-like proteases belonging to Nidovirales have domain III, but with various chain lengths, and 3CL^pro of family Mesoniviridae (family C107) has the same homodimeric structure as that of C30, even though they have no sequence similarity. As a reference, monomeric 3C proteases belonging to the more distant family Picornaviridae (family C3) lacking domain III are compared with C30, and it is shown that the 3C proteases are rigid enough to maintain their structures in the active state.

Supplementary information: The online version contains supplementary material available at 10.1007/s12551-022-01020-x.

Keywords: Chymotrypsin fold; Clan PA; Comparison of protein structures; Protein Data Bank; SARS-CoV-2 3C-like protease.

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Publication types

Review