6WX4

Crystal structure of the SARS CoV-2 Papain-like protease in complex with peptide inhibitor VIR251

Summary for 6WX4

• Entry DOI: 10.2210/pdb6wx4/pdb
• Related: 6WUU
• Related PRD ID: PRD_002390
• Descriptor: Non-structural protein 3, VIR251, ZINC ION, ... (4 entities in total)
• Functional Keywords: covid-19, coronavirus, sars, cov-2, papain-like protease, plpro, deubiquitinating enzyme, ubiquitin, activity-based probe, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV); More
• Total number of polymer chains: 2
• Total formula weight: 37673.08

Authors

Lv, Z.,Olsen, S.K. (deposition date: 2020-05-09, release date: 2020-05-20, Last modification date: 2023-11-15)

Primary citation

Rut, W.,Lv, Z.,Zmudzinski, M.,Patchett, S.,Nayak, D.,Snipas, S.J.,El Oualid, F.,Huang, T.T.,Bekes, M.,Drag, M.,Olsen, S.K.
Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti-COVID-19 drug design.
Sci Adv, 6:-, 2020

PubMed Abstract: Viral papain-like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents a promising target for the development of antiviral drugs. Here, we used a combinatorial substrate library and performed comprehensive activity profiling of SARS-CoV-2 PLpro. On the scaffold of the best hits from positional scanning, we designed optimal fluorogenic substrates and irreversible inhibitors with a high degree of selectivity for SARS PLpro. We determined crystal structures of two of these inhibitors in complex with SARS-CoV-2 PLpro that reveals their inhibitory mechanisms and provides a molecular basis for the observed substrate specificity profiles. Last, we demonstrate that SARS-CoV-2 PLpro harbors deISGylating activity similar to SARSCoV-1 PLpro but its ability to hydrolyze K48-linked Ub chains is diminished, which our sequence and structure analysis provides a basis for. Together, this work has revealed the molecular rules governing PLpro substrate specificity and provides a framework for development of inhibitors with potential therapeutic value or drug repurposing.

PubMed: 33067239
DOI: 10.1126/sciadv.abd4596

Experimental method

X-RAY DIFFRACTION (1.655 Å)