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Publication Abstract from PubMed

The monomeric catalytic domain (residues 1-199) of SARS-CoV-2 main protease (MPro(1-199)) fused to 25 amino acids of its flanking nsp4 region mediates its autoprocessing at the nsp4-MPro(1-199) junction. We report the catalytic activity and the dissociation constants of MPro(1-199) and its analogs with the covalent inhibitors GC373 and nirmatrelvir (NMV), and the estimated monomer-dimer equilibrium constants of these complexes. Mass spectrometry indicates the presence of the accumulated adduct of NMV bound to MPro(WT) and MPro(1-199) and not of GC373. A room temperature crystal structure reveals a native-like fold of the catalytic domain with an unwound oxyanion loop (E state). In contrast, the structure of a covalent complex of the catalytic domain-GC373 or NMV shows an oxyanion loop conformation (E* state) resembling the full-length mature dimer. These results suggest that the E-E* equilibrium modulates autoprocessing of the main protease when converting from a monomeric polyprotein precursor to the mature dimer.

Autoprocessing and oxyanion loop reorganization upon GC373 and nirmatrelvir binding of monomeric SARS-CoV-2 main protease catalytic domain.,Nashed NT, Kneller DW, Coates L, Ghirlando R, Aniana A, Kovalevsky A, Louis JM Commun Biol. 2022 Sep 16;5(1):976. doi: 10.1038/s42003-022-03910-y. PMID:36114420^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.