6AZV

IDO1/BMS-978587 crystal structure

6AZV の概要

• エントリーDOI: 10.2210/pdb6azv/pdb
• 関連するPDBエントリー: 6azu
• 分子名称: Indoleamine 2,3-dioxygenase 1, (1R,2S)-2-(4-[bis(2-methylpropyl)amino]-3-{[(4-methylphenyl)carbamoyl]amino}phenyl)cyclopropane-1-carboxylic acid (3 entities in total)
• 機能のキーワード: ido1 heme-displaced ligand-bound, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm, cytosol : P14902
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 182770.25

構造登録者

Lewis, H.A. (登録日: 2017-09-13, 公開日: 2018-03-21, 最終更新日: 2024-10-23)

主引用文献

Nelp, M.T.,Kates, P.A.,Hunt, J.T.,Newitt, J.A.,Balog, A.,Maley, D.,Zhu, X.,Abell, L.,Allentoff, A.,Borzilleri, R.,Lewis, H.A.,Lin, Z.,Seitz, S.P.,Yan, C.,Groves, J.T.
Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form.
Proc. Natl. Acad. Sci. U.S.A., 115:3249-3254, 2018

PubMed Abstract: For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to -formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme-heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor-enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation.

PubMed: 29531094
DOI: 10.1073/pnas.1719190115

実験手法

X-RAY DIFFRACTION (2.755 Å)