7QY2

X-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 2

7QY2 の概要

• エントリーDOI: 10.2210/pdb7qy2/pdb
• 分子名称: Furin, (2R)-4-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-ium-1-yl]methyl]-6-[3,5-bis(chloranyl)phenyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-ium-1-yl]-2-methyl-butanoate, CALCIUM ION, ... (8 entities in total)
• 機能のキーワード: proprotein convertase, inhibitor, sars-cov-2, protease, complex, furin, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 53721.60

構造登録者

Dahms, S.O.,Brandstetter, H.,Pautsch, A. (登録日: 2022-01-27, 公開日: 2022-04-20, 最終更新日: 2024-11-06)

主引用文献

Dahms, S.O.,Schnapp, G.,Winter, M.,Buttner, F.H.,Schleputz, M.,Gnamm, C.,Pautsch, A.,Brandstetter, H.
Dichlorophenylpyridine-Based Molecules Inhibit Furin through an Induced-Fit Mechanism.
Acs Chem.Biol., 17:816-821, 2022

PubMed Abstract: Inhibitors of the proprotein convertase furin might serve as broad-spectrum antiviral therapeutics. High cellular potency and antiviral activity against acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported for (3,5-dichlorophenyl)pyridine-derived furin inhibitors. Here we characterized the binding mechanism of this inhibitor class using structural, biophysical, and biochemical methods. We established a MALDI-TOF-MS-based furin activity assay, determined IC values, and solved X-ray structures of (3,5-dichlorophenyl)pyridine-derived compounds in complex with furin. The inhibitors induced a substantial conformational rearrangement of the active-site cleft by exposing a central buried tryptophan residue. These changes formed an extended hydrophobic surface patch where the 3,5-dichlorophenyl moiety of the inhibitors was inserted into a newly formed binding pocket. Consistent with these structural rearrangements, we observed slow off-rate binding kinetics and strong structural stabilization in surface plasmon resonance and differential scanning fluorimetry experiments, respectively. The discovered furin conformation offers new opportunities for structure-based drug discovery.

PubMed: 35377598
DOI: 10.1021/acschembio.2c00103

実験手法

X-RAY DIFFRACTION (1.55 Å)