7AH4

Crystal structure of indoleamine 2,3-dioxygenase 1 (IDO1) in complex with ferric heme and MMG-0363

7AH4 の概要

• エントリーDOI: 10.2210/pdb7ah4/pdb
• 関連するPDBエントリー: 6R63 7AH5 7AH6
• 分子名称: Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, 4-chloranyl-2-(2~{H}-1,2,3-triazol-4-yl)aniline, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, dioxygenase, heme-containing enzyme, structure-based drug design, ido1 inhibitor, triazole, small-molecule 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: 97020.46

構造登録者

Roehrig, U.F.,Reynaud, A.,Pojer, F.,Michielin, O.,Zoete, V. (登録日: 2020-09-24, 公開日: 2021-02-17, 最終更新日: 2024-11-06)

主引用文献

Rohrig, U.F.,Majjigapu, S.R.,Reynaud, A.,Pojer, F.,Dilek, N.,Reichenbach, P.,Ascencao, K.,Irving, M.,Coukos, G.,Vogel, P.,Michielin, O.,Zoete, V.
Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.
J.Med.Chem., 64:2205-2227, 2021

PubMed Abstract: The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme-ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds.

PubMed: 33557523
DOI: 10.1021/acs.jmedchem.0c01968

実験手法

X-RAY DIFFRACTION (2.401 Å)