7CJM

SARS CoV-2 PLpro in complex with GRL0617

Summary for 7CJM

• Entry DOI: 10.2210/pdb7cjm/pdb
• Descriptor: Non-structural protein 3, 5-amino-2-methyl-N-[(1R)-1-naphthalen-1-ylethyl]benzamide, ZINC ION (3 entities in total)
• Functional Keywords: plpro-c111s, grl0617, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 1
• Total formula weight: 36227.13

Authors

Fu, Z.,Huang, H. (deposition date: 2020-07-11, release date: 2020-09-02, Last modification date: 2024-10-16)

Primary citation

Fu, Z.,Huang, B.,Tang, J.,Liu, S.,Liu, M.,Ye, Y.,Liu, Z.,Xiong, Y.,Zhu, W.,Cao, D.,Li, J.,Niu, X.,Zhou, H.,Zhao, Y.J.,Zhang, G.,Huang, H.
The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery.
Nat Commun, 12:488-488, 2021

PubMed Abstract: SARS-CoV-2 is the pathogen responsible for the COVID-19 pandemic. The SARS-CoV-2 papain-like cysteine protease (PLpro) has been implicated in playing important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses. The multiple functions of PLpro render it a promising drug target. Therefore, we screened a library of approved drugs and also examined available inhibitors against PLpro. Inhibitor GRL0617 showed a promising in vitro IC of 2.1 μM and an effective antiviral inhibition in cell-based assays. The co-crystal structure of SARS-CoV-2 PLpro in complex with GRL0617 indicates that GRL0617 is a non-covalent inhibitor and it resides in the ubiquitin-specific proteases (USP) domain of PLpro. NMR data indicate that GRL0617 blocks the binding of ISG15 C-terminus to PLpro. Using truncated ISG15 mutants, we show that the C-terminus of ISG15 plays a dominant role in binding PLpro. Structural analysis reveals that the ISG15 C-terminus binding pocket in PLpro contributes a disproportionately large portion of binding energy, thus this pocket is a hot spot for antiviral drug discovery targeting PLpro.

PubMed: 33473130
DOI: 10.1038/s41467-020-20718-8

Experimental method

X-RAY DIFFRACTION (3.2 Å)