5WN8

Structural Insights into Substrate and Inhibitor Binding Sites in Human Indoleamine 2,3-Dioxygenase 1

5WN8 の概要

• エントリーDOI: 10.2210/pdb5wn8/pdb
• 関連するPDBエントリー: 5WMU 5WMV 5WMW 5WMX
• 分子名称: Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-{[2-(sulfamoylamino)ethyl]amino}-1,2,5-oxadiazole-3-carboximidamide, ... (4 entities in total)
• 機能のキーワード: indoleamine 2, 3-dioxygenase 1 tryptophan heme inhibitor epacadostat incb024360, oxidoreductase
• 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: 97693.28

構造登録者

Lewis-Ballester, A.,Pham, K.N.,Batabyal, D.,Karkashon, S.,Bonanno, J.B.,Poulos, T.L.,Yeh, S.R. (登録日: 2017-07-31, 公開日: 2017-12-06, 最終更新日: 2024-10-23)

主引用文献

Lewis-Ballester, A.,Pham, K.N.,Batabyal, D.,Karkashon, S.,Bonanno, J.B.,Poulos, T.L.,Yeh, S.R.
Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1.
Nat Commun, 8:1693-1693, 2017

PubMed Abstract: Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape. However, drug development has been hindered by limited structural information. Here, we report the crystal structures of hIDO1 in complex with its substrate, Trp, an inhibitor, epacadostat, and/or an effector, indole ethanol (IDE). The data reveal structural features of the active site (Sa) critical for substrate activation; in addition, they disclose a new inhibitor-binding mode and a distinct small molecule binding site (Si). Structure-guided mutation of a critical residue, F270, to glycine perturbs the Si site, allowing structural determination of an inhibitory complex, where both the Sa and Si sites are occupied by Trp. The Si site offers a novel target site for allosteric inhibitors and a molecular explanation for the previously baffling substrate-inhibition behavior of the enzyme. Taken together, the data open exciting new avenues for structure-based drug design.

PubMed: 29167421
DOI: 10.1038/s41467-017-01725-8

実験手法

X-RAY DIFFRACTION (2.5 Å)