7TFR

Room temperature X-ray structure of SARS-CoV-2 main protease (3CL Mpro) in complex with NBH-2

Summary for 7TFR

• Entry DOI: 10.2210/pdb7tfr/pdb
• Related: 7TEH
• Descriptor: 3C-like proteinase, (1R,2S,5S)-N-{(1Z,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-({1-[(2-methylpropane-2-sulfonyl)methyl]cyclohexyl}carbamoyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (3 entities in total)
• Functional Keywords: sars-cov-2 main protease, homodimer, cysteine protease, covalent inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 34490.45

Authors

Kovalevsky, A.,Kneller, D.W.,Coates, L. (deposition date: 2022-01-07, release date: 2022-03-02, Last modification date: 2024-11-20)

Primary citation

Kneller, D.W.,Li, H.,Phillips, G.,Weiss, K.L.,Zhang, Q.,Arnould, M.A.,Jonsson, C.B.,Surendranathan, S.,Parvathareddy, J.,Blakeley, M.P.,Coates, L.,Louis, J.M.,Bonnesen, P.V.,Kovalevsky, A.
Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease
Nat Commun, 13:2268-, 2022

PubMed Abstract: Emerging SARS-CoV-2 variants continue to threaten the effectiveness of COVID-19 vaccines, and small-molecule antivirals can provide an important therapeutic treatment option. The viral main protease (M) is critical for virus replication and thus is considered an attractive drug target. We performed the design and characterization of three covalent hybrid inhibitors BBH-1, BBH-2 and NBH-2 created by splicing components of hepatitis C protease inhibitors boceprevir and narlaprevir, and known SARS-CoV-1 protease inhibitors. A joint X-ray/neutron structure of the M/BBH-1 complex demonstrates that a Cys145 thiolate reaction with the inhibitor's keto-warhead creates a negatively charged oxyanion. Protonation states of the ionizable residues in the M active site adapt to the inhibitor, which appears to be an intrinsic property of M. Structural comparisons of the hybrid inhibitors with PF-07321332 reveal unconventional F···O interactions of PF-07321332 with M which may explain its more favorable enthalpy of binding. BBH-1, BBH-2 and NBH-2 exhibit comparable antiviral properties in vitro relative to PF-07321332, making them good candidates for further design of improved antivirals.

PubMed: 35477935
DOI: 10.1038/s41467-022-29915-z

Experimental method

X-RAY DIFFRACTION (1.8 Å)