RT Journal Article
SR Electronic
T1 Inhibitor Binding Modulates Protonation States in the Active Site of SARS-CoV-2 Main Protease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.12.426388
DO 10.1101/2021.01.12.426388
A1 Daniel W. Kneller
A1 Gwyndalyn Phillips
A1 Kevin L. Weiss
A1 Qiu Zhang
A1 Leighton Coates
A1 Andrey Kovalevsky
YR 2021
UL http://biorxiv.org/content/early/2021/01/12/2021.01.12.426388.abstract
AB The main protease (3CL Mpro) from 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. Although drugs have been developed to inhibit the proteases from HIV, hepatitis C and other viruses, no such therapeutic is available to inhibit the main protease of SARS-CoV-2. To directly observe the protonation states in SARS-CoV-2 Mpro and to elucidate their importance in inhibitor binding, we determined the structure of the enzyme in complex with the α-ketoamide inhibitor telaprevir using neutron protein crystallography at near-physiological temperature. We compared protonation states in the inhibitor complex with those determined for a ligand-free neutron structure of Mpro. This comparison revealed that three active-site histidine residues (His41, His163 and His164) adapt to ligand binding, altering their protonation states to accommodate binding of telaprevir. We suggest that binding of other α-ketoamide inhibitors can lead to the same protonation state changes of the active site histidine residues. Thus, by studying the role of active site protonation 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 Mpro.Competing Interest StatementThe authors have declared no competing interest.