6YVA

PLpro-C111S with mISG15

Summary for 6YVA

• Entry DOI: 10.2210/pdb6yva/pdb
• Descriptor: Replicase polyprotein 1a, Ubiquitin-like protein ISG15, ZINC ION, ... (4 entities in total)
• Functional Keywords: deubiquitinase, papain-like-protease, sars-cov-2, isg15, complex, cell invasion
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV); More
• Total number of polymer chains: 2
• Total formula weight: 53640.48

Authors

Shin, D.,Dikic, I. (deposition date: 2020-04-28, release date: 2020-05-13, Last modification date: 2024-01-24)

Primary citation

Shin, D.,Mukherjee, R.,Grewe, D.,Bojkova, D.,Baek, K.,Bhattacharya, A.,Schulz, L.,Widera, M.,Mehdipour, A.R.,Tascher, G.,Geurink, P.P.,Wilhelm, A.,van der Heden van Noort, G.J.,Ovaa, H.,Muller, S.,Knobeloch, K.P.,Rajalingam, K.,Schulman, B.A.,Cinatl, J.,Hummer, G.,Ciesek, S.,Dikic, I.
Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity.
Nature, 587:657-662, 2020

PubMed Abstract: The papain-like protease PLpro is an essential coronavirus enzyme that is required for processing viral polyproteins to generate a functional replicase complex and enable viral spread. PLpro is also implicated in cleaving proteinaceous post-translational modifications on host proteins as an evasion mechanism against host antiviral immune responses. Here we perform biochemical, structural and functional characterization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PLpro (SCoV2-PLpro) and outline differences with SARS-CoV PLpro (SCoV-PLpro) in regulation of host interferon and NF-κB pathways. SCoV2-PLpro and SCoV-PLpro share 83% sequence identity but exhibit different host substrate preferences; SCoV2-PLpro preferentially cleaves the ubiquitin-like interferon-stimulated gene 15 protein (ISG15), whereas SCoV-PLpro predominantly targets ubiquitin chains. The crystal structure of SCoV2-PLpro in complex with ISG15 reveals distinctive interactions with the amino-terminal ubiquitin-like domain of ISG15, highlighting the high affinity and specificity of these interactions. Furthermore, upon infection, SCoV2-PLpro contributes to the cleavage of ISG15 from interferon responsive factor 3 (IRF3) and attenuates type I interferon responses. Notably, inhibition of SCoV2-PLpro with GRL-0617 impairs the virus-induced cytopathogenic effect, maintains the antiviral interferon pathway and reduces viral replication in infected cells. These results highlight a potential dual therapeutic strategy in which targeting of SCoV2-PLpro can suppress SARS-CoV-2 infection and promote antiviral immunity.

PubMed: 32726803
DOI: 10.1038/s41586-020-2601-5

Experimental method

X-RAY DIFFRACTION (3.18 Å)