9ATA

Crystal structure of MERS 3CL protease in complex with a phenylethyl 2-pyrrolidone inhibitor

This is a non-PDB format compatible entry.

Summary for 9ATA

• Entry DOI: 10.2210/pdb9ata/pdb
• Descriptor: 3C-like proteinase nsp5, (1S,2S)-1-hydroxy-2-{[N-({[(2S)-5-oxo-1-(2-phenylethyl)pyrrolidin-2-yl]methoxy}carbonyl)-L-leucyl]amino}-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid, (1R,2S)-1-hydroxy-2-{[N-({[(2S)-5-oxo-1-(2-phenylethyl)pyrrolidin-2-yl]methoxy}carbonyl)-L-leucyl]amino}-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid, ... (4 entities in total)
• Functional Keywords: mers, 3cl protease inhibitors, covid-19, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Middle East respiratory syndrome-related coronavirus
• Total number of polymer chains: 2
• Total formula weight: 71015.26

Authors

Liu, L.,Lovell, S.,Battaile, K.P.,Dampalla, C.S.,Groutas, W.C. (deposition date: 2024-02-26, release date: 2024-07-10, Last modification date: 2024-08-07)

Primary citation

Dampalla, C.S.,Kim, Y.,Zabiegala, A.,Howard, D.J.,Nguyen, H.N.,Madden, T.K.,Thurman, H.A.,Cooper, A.,Liu, L.,Battaile, K.P.,Lovell, S.,Chang, K.O.,Groutas, W.C.
Structure-Guided Design of Potent Coronavirus Inhibitors with a 2-Pyrrolidone Scaffold: Biochemical, Crystallographic, and Virological Studies.
J.Med.Chem., 67:11937-11956, 2024

PubMed Abstract: Zoonotic coronaviruses are known to produce severe infections in humans and have been the cause of significant morbidity and mortality worldwide. SARS-CoV-2 was the largest and latest contributor of fatal cases, even though MERS-CoV has the highest case-fatality ratio among zoonotic coronaviruses. These infections pose a high risk to public health worldwide warranting efforts for the expeditious discovery of antivirals. Hence, we hereby describe a novel series of inhibitors of coronavirus 3CL embodying an -substituted 2-pyrrolidone scaffold envisaged to exploit favorable interactions with the S3-S4 subsites and connected to an invariant Leu-Gln 2-P1 recognition element. Several inhibitors showed nanomolar antiviral activity in enzyme and cell-based assays, with no significant cytotoxicity. High-resolution crystal structures of inhibitors bound to the 3CL were determined to probe and identify the molecular determinants associated with binding, to inform the structure-guided optimization of the inhibitors, and to confirm the mechanism of action of the inhibitors.

PubMed: 38953866
DOI: 10.1021/acs.jmedchem.4c00551

Experimental method

X-RAY DIFFRACTION (1.65 Å)