7LFU

Crystal structure of the SARS CoV-1 Papain-like protease in complex with peptide inhibitor VIR250

Summary for 7LFU

• Entry DOI: 10.2210/pdb7lfu/pdb
• Related PRD ID: PRD_002385
• Descriptor: papain-like protease, Papain-like protease peptide inhibitor VIR250 (2 entities in total)
• Functional Keywords: covid-19, coronavirus, sars, cov-1, 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 (SARS-CoV); More
• Total number of polymer chains: 2
• Total formula weight: 37193.13

Authors

Olsen, S.K.,Lv, Z. (deposition date: 2021-01-18, release date: 2021-11-10, Last modification date: 2023-11-15)

Primary citation

Patchett, S.,Lv, Z.,Rut, W.,Bekes, M.,Drag, M.,Olsen, S.K.,Huang, T.T.
A molecular sensor determines the ubiquitin substrate specificity of SARS-CoV-2 papain-like protease.
Cell Rep, 36:109754-109754, 2021

PubMed Abstract: The SARS-CoV-2 papain-like protease (PLpro) is a target for antiviral drug development. It is essential for processing viral polyproteins for replication and functions in host immune evasion by cleaving ubiquitin (Ub) and ubiquitin-like protein (Ubl) conjugates. While highly conserved, SARS-CoV-2 and SARS-CoV PLpro have contrasting Ub/Ubl substrate preferences. Using a combination of structural analyses and functional assays, we identify a molecular sensor within the S1 Ub-binding site of PLpro that serves as a key determinant of substrate specificity. Variations within the S1 sensor specifically alter cleavage of Ub substrates but not of the Ubl interferon-stimulated gene 15 protein (ISG15). Significantly, a variant of concern associated with immune evasion carries a mutation in the S1 sensor that enhances PLpro activity on Ub substrates. Collectively, our data identify the S1 sensor region as a potential hotspot of variability that could alter host antiviral immune responses to newly emerging SARS-CoV-2 lineages.

PubMed: 34547223
DOI: 10.1016/j.celrep.2021.109754

Experimental method

X-RAY DIFFRACTION (2.29 Å)