7JRN

Crystal structure of the wild type SARS-CoV-2 papain-like protease (PLPro) with inhibitor GRL0617

Summary for 7JRN

• Entry DOI: 10.2210/pdb7jrn/pdb
• Descriptor: Non-structural protein 3, 5-amino-2-methyl-N-[(1R)-1-naphthalen-1-ylethyl]benzamide, ZINC ION, ... (5 entities in total)
• Functional Keywords: covid, covid19, covid-19, sars, sars cov2, cov, ncov 19, coronavirus, main protease, 3cl, mpro, pro, viral protein, gc376, calpain inhibitor ii, leupeptin, calpain, aldehyde, gc-376, 3cl-like, a-ketoamide, alpheketoamide, alpha, ketoamide, peptidomimetic, protease, cysteine, hydrolase-hydrolase inhibitor complex, grl0617, papin-like protease, plp, plpro, pl-pro, papain
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 2
• Total formula weight: 74705.19

Authors

Sacco, M.,Ma, C.,Wang, J.,Chen, Y. (deposition date: 2020-08-12, release date: 2020-08-26, Last modification date: 2023-10-18)

Primary citation

Ma, C.,Sacco, M.D.,Xia, Z.,Lambrinidis, G.,Townsend, J.A.,Hu, Y.,Meng, X.,Szeto, T.,Ba, M.,Zhang, X.,Gongora, M.,Zhang, F.,Marty, M.T.,Xiang, Y.,Kolocouris, A.,Chen, Y.,Wang, J.
Discovery of SARS-CoV-2 Papain-like Protease Inhibitors through a Combination of High-Throughput Screening and a FlipGFP-Based Reporter Assay.
Acs Cent.Sci., 7:1245-1260, 2021

PubMed Abstract: The papain-like protease (PL) of SARS-CoV-2 is a validated antiviral drug target. Through a fluorescence resonance energy transfer-based high-throughput screening and subsequent lead optimization, we identified several PL inhibitors including and with improved enzymatic inhibition and antiviral activity compared to , which was reported as a SARS-CoV PL inhibitor. Significantly, we developed a cell-based FlipGFP assay that can be applied to predict the cellular antiviral activity of PL inhibitors in the BSL-2 setting. X-ray crystal structure of PL in complex with showed that binding of to SARS-CoV-2 induced a conformational change in the BL2 loop to a more closed conformation. Molecular dynamics simulations showed that and engaged in more extensive interactions than . Overall, the PL inhibitors identified in this study represent promising candidates for further development as SARS-CoV-2 antivirals, and the FlipGFP-PL assay is a suitable surrogate for screening PL inhibitors in the BSL-2 setting.

PubMed: 34341772
DOI: 10.1021/acscentsci.1c00519

Experimental method

X-RAY DIFFRACTION (2.48 Å)