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Autoprocessing and oxyanion loop reorganization upon GC373 and nirmatrelvir binding of monomeric SARS-CoV-2 main protease catalytic domain.
Nashed, Nashaat T; Kneller, Daniel W; Coates, Leighton; Ghirlando, Rodolfo; Aniana, Annie; Kovalevsky, Andrey; Louis, John M.
  • Nashed NT; Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892-0520, USA.
  • Kneller DW; Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, TN, 37831, USA.
  • Coates L; Second Target Station, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, TN, 37831, USA.
  • Ghirlando R; Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892-0520, USA.
  • Aniana A; Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892-0520, USA.
  • Kovalevsky A; Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, TN, 37831, USA. kovalevskyay@ornl.gov.
  • Louis JM; Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892-0520, USA. johnl@niddk.nih.gov.
Commun Biol ; 5(1): 976, 2022 09 16.
Article in English | MEDLINE | ID: covidwho-2036926
ABSTRACT
The monomeric catalytic domain (residues 1-199) of SARS-CoV-2 main protease (MPro1-199) fused to 25 amino acids of its flanking nsp4 region mediates its autoprocessing at the nsp4-MPro1-199 junction. We report the catalytic activity and the dissociation constants of MPro1-199 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 MProWT and MPro1-199 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Limits: Humans Language: English Journal: Commun Biol Year: 2022 Document Type: Article Affiliation country: S42003-022-03910-y

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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Limits: Humans Language: English Journal: Commun Biol Year: 2022 Document Type: Article Affiliation country: S42003-022-03910-y