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Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin.
Wydorski, Pawel M; Osipiuk, Jerzy; Lanham, Benjamin T; Tesar, Christine; Endres, Michael; Engle, Elizabeth; Jedrzejczak, Robert; Mullapudi, Vishruth; Michalska, Karolina; Fidelis, Krzysztof; Fushman, David; Joachimiak, Andrzej; Joachimiak, Lukasz A.
  • Wydorski PM; Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • Osipiuk J; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • Lanham BT; Center for Structural Biology of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, 60667, USA.
  • Tesar C; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Lemont, IL, 60439, USA.
  • Endres M; Department of Chemistry and Biochemistry, Center for Biomolecular Structure and Organization, University of Maryland, College Park, MD, 20742, USA.
  • Engle E; Center for Structural Biology of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, 60667, USA.
  • Jedrzejczak R; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Lemont, IL, 60439, USA.
  • Mullapudi V; Center for Structural Biology of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, 60667, USA.
  • Michalska K; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Lemont, IL, 60439, USA.
  • Fidelis K; Department of Chemistry and Biochemistry, Center for Biomolecular Structure and Organization, University of Maryland, College Park, MD, 20742, USA.
  • Fushman D; Center for Structural Biology of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, 60667, USA.
  • Joachimiak A; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Lemont, IL, 60439, USA.
  • Joachimiak LA; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Nat Commun ; 14(1): 2366, 2023 04 25.
Article in English | MEDLINE | ID: covidwho-2305876
ABSTRACT
The Papain-like protease (PLpro) is a domain of a multi-functional, non-structural protein 3 of coronaviruses. PLpro cleaves viral polyproteins and posttranslational conjugates with poly-ubiquitin and protective ISG15, composed of two ubiquitin-like (UBL) domains. Across coronaviruses, PLpro showed divergent selectivity for recognition and cleavage of posttranslational conjugates despite sequence conservation. We show that SARS-CoV-2 PLpro binds human ISG15 and K48-linked di-ubiquitin (K48-Ub2) with nanomolar affinity and detect alternate weaker-binding modes. Crystal structures of untethered PLpro complexes with ISG15 and K48-Ub2 combined with solution NMR and cross-linking mass spectrometry revealed how the two domains of ISG15 or K48-Ub2 are differently utilized in interactions with PLpro. Analysis of protein interface energetics predicted differential binding stabilities of the two UBL/Ub domains that were validated experimentally. We emphasize how substrate recognition can be tuned to cleave specifically ISG15 or K48-Ub2 modifications while retaining capacity to cleave mono-Ub conjugates. These results highlight alternative druggable surfaces that would inhibit PLpro function.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Ubiquitin / SARS-CoV-2 / COVID-19 Type of study: Prognostic study / Randomized controlled trials Limits: Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2023 Document Type: Article Affiliation country: S41467-023-38031-5

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Ubiquitin / SARS-CoV-2 / COVID-19 Type of study: Prognostic study / Randomized controlled trials Limits: Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2023 Document Type: Article Affiliation country: S41467-023-38031-5