7S6O

The crystal structure of Lys48-linked di-ubiquitin

7S6O の概要

• エントリーDOI: 10.2210/pdb7s6o/pdb
• 関連するPDBエントリー: 3NS8
• 分子名称: Ubiquitin, ACETATE ION, ... (4 entities in total)
• 機能のキーワード: ubiquitin, di-ubiquitin, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 17414.85

構造登録者

Osipiuk, J.,Tesar, C.,Lanham, B.T.,Wydorski, P.,Fushman, D.,Joachimiak, L.,Joachimiak, A. (登録日: 2021-09-14, 公開日: 2021-09-22, 最終更新日: 2023-10-25)

主引用文献

Wydorski, P.M.,Osipiuk, J.,Lanham, B.T.,Tesar, C.,Endres, M.,Engle, E.,Jedrzejczak, R.,Mullapudi, V.,Michalska, K.,Fidelis, K.,Fushman, D.,Joachimiak, A.,Joachimiak, L.A.
Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin.
Nat Commun, 14:2366-2366, 2023

PubMed 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-Ub) with nanomolar affinity and detect alternate weaker-binding modes. Crystal structures of untethered PLpro complexes with ISG15 and K48-Ub combined with solution NMR and cross-linking mass spectrometry revealed how the two domains of ISG15 or K48-Ub 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-Ub modifications while retaining capacity to cleave mono-Ub conjugates. These results highlight alternative druggable surfaces that would inhibit PLpro function.

PubMed: 37185902
DOI: 10.1038/s41467-023-38031-5

実験手法

X-RAY DIFFRACTION (1.25 Å)