6DPQ

Mapping the binding trajectory of a suicide inhibitor in human indoleamine 2,3-dioxygenase 1

6DPQ の概要

• エントリーDOI: 10.2210/pdb6dpq/pdb
• 関連するPDBエントリー: 5WMV 5WMW 5WMX 5WN8 6DPR
• 分子名称: Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: indoleamine 2, 3-dioxygenase, heme-containing enzyme, bms-986205, structure-based design, hido1-selective inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 97163.80

構造登録者

Pham, K.N.,Yeh, S.R. (登録日: 2018-06-09, 公開日: 2018-11-07, 最終更新日: 2024-11-06)

主引用文献

Pham, K.N.,Yeh, S.R.
Mapping the Binding Trajectory of a Suicide Inhibitor in Human Indoleamine 2,3-Dioxygenase 1.
J. Am. Chem. Soc., 140:14538-14541, 2018

PubMed Abstract: Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an important heme-containing enzyme that is a key drug target for cancer immunotherapy. Several hIDO1 inhibitors have entered clinical trials, among which BMS-986205 (BMS) stands out as the only suicide inhibitor. Despite its "best-in-class" activity, the action mechanism of BMS remains elusive. Here, we report three crystal structures of hIDO1-BMS complexes that define the complete binding trajectory of the inhibitor. BMS first binds in a solvent exposed surface cleft near the active site in an extended conformation. The initial binding partially unfolds the active site, which triggers heme release, thereby exposing a new binding pocket. The inhibitor then undergoes a large scale movement to this new binding pocket, where it binds by adopting a high energy kinked conformation. Finally, the inhibitor relaxes to a bent conformation, via an additional large scale rearrangement, culminating in the energy minimum state. The structural data offer a molecular explanation for the remarkable efficacy and suicide inhibition activity of the inhibitor. They also suggest a novel strategy that can be applied for drug development targeting hIDO1 and related enzymes.

PubMed: 30347977
DOI: 10.1021/jacs.8b07994

実験手法

X-RAY DIFFRACTION (2.94 Å)