7QCI

Structure of SARS-CoV-2 Papain-like Protease bound to N-(3,4-dihydroxybenzylidene)-thiosemicarbazone

7QCI の概要

• エントリーDOI: 10.2210/pdb7qci/pdb
• 分子名称: Papain-like protease nsp3, N-(3,4-dihydroxybenzylidene)-thiosemicarbazone, GLYCEROL, ... (7 entities in total)
• 機能のキーワード: cystein-protease, inhibitor, sars-cov-2, hydrazone, deubiquitination, hydrolase
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36686.70

構造登録者

Ewert, W.,Gunther, S.,Reinke, P.,Falke, S.,Lieske, J.,Miglioli, F.,Carcelli, M.,Srinivasan, V.,Betzel, C.,Han, H.,Lorenzen, K.,Guenther, C.,Niebling, S.,Garcia-Alai, M.,Hinrichs, W.,Rogolino, D.,Meents, A. (登録日: 2021-11-24, 公開日: 2022-03-16, 最終更新日: 2024-01-31)

主引用文献

Ewert, W.,Gunther, S.,Miglioli, F.,Falke, S.,Reinke, P.Y.A.,Niebling, S.,Gunther, C.,Han, H.,Srinivasan, V.,Brognaro, H.,Lieske, J.,Lorenzen, K.,Garcia-Alai, M.M.,Betzel, C.,Carcelli, M.,Hinrichs, W.,Rogolino, D.,Meents, A.
Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease.
Front Chem, 10:832431-832431, 2022

PubMed Abstract: The papain-like protease (PLpro) of SARS-CoV-2 is essential for viral propagation and, additionally, dysregulation of the host innate immune system. Using a library of 40 potential metal-chelating compounds we performed an X-ray crystallographic screening against PLpro. As outcome we identified six compounds binding to the target protein. Here we describe the interaction of one hydrazone (H1) and five thiosemicarbazone (T1-T5) compounds with the two distinct natural substrate binding sites of PLpro for ubiquitin and ISG15. H1 binds to a polar groove at the S1 binding site by forming several hydrogen bonds with PLpro. T1-T5 bind into a deep pocket close to the polyubiquitin and ISG15 binding site S2. Their interactions are mainly mediated by multiple hydrogen bonds and further hydrophobic interactions. In particular compound H1 interferes with natural substrate binding by sterical hindrance and induces conformational changes in protein residues involved in substrate binding, while compounds T1-T5 could have a more indirect effect. Fluorescence based enzyme activity assay and complementary thermal stability analysis reveal only weak inhibition properties in the high micromolar range thereby indicating the need for compound optimization. Nevertheless, the unique binding properties involving strong hydrogen bonding and the various options for structural optimization make the compounds ideal lead structures. In combination with the inexpensive and undemanding synthesis, the reported hydrazone and thiosemicarbazones represent an attractive scaffold for further structure-based development of novel PLpro inhibitors by interrupting protein-protein interactions at the S1 and S2 site.

PubMed: 35480391
DOI: 10.3389/fchem.2022.832431

実験手法

X-RAY DIFFRACTION (1.76 Å)