7W9G

Complex structure of Mpro with ebselen-derivative inhibitor

Summary for 7W9G

• Entry DOI: 10.2210/pdb7w9g/pdb
• Descriptor: 3C-like proteinase nsp5, SELENIUM ATOM (3 entities in total)
• Functional Keywords: protease, cov-2, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 33991.58

Authors

Sahoo, P.,Kumar, A. (deposition date: 2021-12-09, release date: 2022-12-14, Last modification date: 2023-11-29)

Primary citation

Sahoo, P.,Lenka, D.R.,Batabyal, M.,Pain, P.K.,Kumar, S.,Manna, D.,Kumar, A.
Detailed Insights into the Inhibitory Mechanism of New Ebselen Derivatives against Main Protease (M pro ) of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2).
Acs Pharmacol Transl Sci, 6:171-180, 2023

PubMed Abstract: SARS-CoV-2 main protease (M/3CL) is a crucial target for therapeutics, which is responsible for viral polyprotein cleavage and plays a vital role in virus replication and survival. Recent studies suggest that 2-phenylbenzisoselenazol-3(2)-one (ebselen) is a potent covalent inhibitor of M, which affects its enzymatic activity and virus survival. Herein, we synthesized various ebselen derivatives to understand the mechanism of M inhibition by ebselen. Using ebselen derivatives, we characterized the detailed interaction mechanism with M. We discovered that modification of the parent ebselen inhibitor with an electron-withdrawing group (NO) increases the inhibition efficacy by 2-fold. We also solved the structure of an M complex with an ebselen derivative showing the mechanism of inhibition by blocking the catalytic Cys145 of M. Using a combination of crystal structures and LC-MS data, we showed that M hydrolyzes the new ebselen derivative and leaves behind selenium (Se) bound with Cys145 of the catalytic dyad of M. We also described the binding profile of ebselen-based inhibitors using molecular modeling predictions supported by binding and inhibition assays. Furthermore, we have also solved the crystal structure of catalytically inactive mutant H41N-M, which represents the inactive state of the protein where the substrate binding pocket is blocked. The inhibited structure of H41N-M shows gatekeeper residues in the substrate binding pocket responsible for blocking the substrate binding; mutation of these gatekeeper residues leads to hyperactive M.

PubMed: 36650888
DOI: 10.1021/acsptsci.2c00203

Experimental method

X-RAY DIFFRACTION (2.5 Å)