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8B4X

X-ray structure of furin (PCSK3) in complex with Guanidinomethyl-Phac-R-Tle-K-6-(aminomethyl)-3-amino-isoindol

8B4X の概要
エントリーDOI10.2210/pdb8b4x/pdb
分子名称Furin, Guanidinomethyl-Phac-R-Tle-K-6-(aminomethyl)-3-amino-isoindol, CALCIUM ION, ... (7 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)
詳細
タンパク質・核酸の鎖数2
化学式量合計53267.18
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: 2024-05-15)
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
Cited by
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 benzamidinederived furin inhibitors.
PubMed: 38385828
DOI: 10.1002/cmdc.202400057
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (1.6 Å)
構造検証レポート
Validation report summary of 8b4x
検証レポート(詳細版)ダウンロードをダウンロード

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件を2025-06-25に公開中

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