7LB7

Joint X-ray/neutron structure of SARS-CoV-2 main protease (3CL Mpro) in complex with Telaprevir

Summary for 7LB7

• Entry DOI: 10.2210/pdb7lb7/pdb
• Descriptor: 3C-like proteinase, (1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(2R,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-1-carboxamide (3 entities in total)
• Functional Keywords: cysteine protease, dimer, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV,SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 34507.41

Authors

Kovalevsky, A.Y.,Kneller, D.W.,Coates, L. (deposition date: 2021-01-07, release date: 2021-01-20, Last modification date: 2024-11-13)

Primary citation

Kneller, D.W.,Phillips, G.,Weiss, K.L.,Zhang, Q.,Coates, L.,Kovalevsky, A.
Direct Observation of Protonation State Modulation in SARS-CoV-2 Main Protease upon Inhibitor Binding with Neutron Crystallography.
J.Med.Chem., 64:4991-5000, 2021

PubMed Abstract: The main protease (3CL M) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. To date, no small-molecule clinical drugs are available that specifically inhibit SARS-CoV-2 M. To aid rational drug design, we determined a neutron structure of M in complex with the α-ketoamide inhibitor telaprevir at near-physiological (22 °C) temperature. We directly observed protonation states in the inhibitor complex and compared them with those in the ligand-free M, revealing modulation of the active-site protonation states upon telaprevir binding. We suggest that binding of other α-ketoamide covalent inhibitors can lead to the same protonation state changes in the M active site. Thus, by studying the protonation state changes induced by inhibitors, we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 M.

PubMed: 33755450
DOI: 10.1021/acs.jmedchem.1c00058

Experimental method

NEUTRON DIFFRACTION (2.4 Å)
X-RAY DIFFRACTION (2 Å)