8B4W

X-ray structure of furin (PCSK3) in complex with 1H-isoindol-3-amine

8B4W の概要

• エントリーDOI: 10.2210/pdb8b4w/pdb
• 分子名称: Furin, 1H-isoindol-3-amine, CALCIUM ION, ... (8 entities in total)
• 機能のキーワード: furin, proprotein convertase subtilisin/kexin type 3, pcsk3, sars-cov-2, inhibitor, protease, complex, 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: 53212.05

構造登録者

Dahms, S.O.,Brandstetter, H. (登録日: 2022-09-21, 公開日: 2023-10-04, 最終更新日: 2024-11-13)

主引用文献

Lange, R.W.,Bloch, K.,Heindl, M.R.,Wollenhaupt, J.,Weiss, M.S.,Brandstetter, H.,Klebe, G.,Falcone, F.H.,Bottcher-Friebertshauser, E.,Dahms, S.O.,Steinmetzer, T.
Fragment-Based Design, Synthesis, and Characterization of Aminoisoindole-Derived Furin Inhibitors.
Chemmedchem, 19:e202400057-e202400057, 2024

PubMed Abstract: A 1H-isoindol-3-amine was identified as suitable P1 group for the proprotein convertase furin using a crystallographic screening with a set of 20 fragments known to occupy the S1 pocket of trypsin-like serine proteases. Its binding mode is very similar to that observed for the P1 group of benzamidine-derived peptidic furin inhibitors suggesting an aminomethyl substitution of this fragment to obtain a couplable P1 residue for the synthesis of substrate-analogue furin inhibitors. The obtained inhibitors possess a slightly improved picomolar inhibitory potency compared to their benzamidine-derived analogues. The crystal structures of two inhibitors in complex with furin revealed that the new P1 group is perfectly suited for incorporation in peptidic furin inhibitors. Selected inhibitors were tested for antiviral activity against respiratory syncytial virus (RSV) and a furin-dependent influenza A virus (SC35M/H7N7) in A549 human lung cells and demonstrated an efficient inhibition of virus activation and replication at low micromolar or even submicromolar concentrations. First results suggest that the Mas-related G-protein coupled receptor GPCR-X2 could be a potential off-target for certain benzamidine-derived furin inhibitors.

PubMed: 38385828
DOI: 10.1002/cmdc.202400057

実験手法

X-RAY DIFFRACTION (1.6 Å)