6R63

Crystal structure of indoleamine 2,3-dioxygenase 1 (IDO1) in complex with ferric heme and MMG-0358

6R63 の概要

• エントリーDOI: 10.2210/pdb6r63/pdb
• 分子名称: Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, 4-chloranyl-2-(2~{H}-1,2,3-triazol-4-yl)phenol (3 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: 96828.79

構造登録者

Roehrig, U.F.,Reynaud, A.,Pojer, F.,Michielin, O.,Zoete, V. (登録日: 2019-03-26, 公開日: 2019-10-02, 最終更新日: 2024-10-09)

主引用文献

Rohrig, U.F.,Reynaud, A.,Majjigapu, S.R.,Vogel, P.,Pojer, F.,Zoete, V.
Inhibition Mechanisms of Indoleamine 2,3-Dioxygenase 1 (IDO1).
J.Med.Chem., 62:8784-8795, 2019

PubMed Abstract: Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the rate-limiting step in the kynurenine pathway of tryptophan metabolism, which is involved in immunity, neuronal function, and aging. Its implication in pathologies such as cancer and neurodegenerative diseases has stimulated the development of IDO1 inhibitors. However, negative phase III clinical trial results of the IDO1 inhibitor epacadostat in cancer immunotherapy call for a better understanding of the role and the mechanisms of IDO1 inhibition. In this work, we investigate the molecular inhibition mechanisms of four known IDO1 inhibitors and of two quinones in detail, using different experimental and computational approaches. We also determine for the first time the X-ray structure of the highly efficient 1,2,3-triazole inhibitor MMG-0358. Based on our results and a comprehensive literature overview, we propose a classification scheme for IDO1 inhibitors according to their inhibition mechanism, which will be useful for further developments in the field.

PubMed: 31525930
DOI: 10.1021/acs.jmedchem.9b00942

実験手法

X-RAY DIFFRACTION (2.894 Å)