9UZ1

Crystal structure of the indoleamine 2,3-dioxygenagse 2 (IDO2) H143Y mutant complexed with L-Trp

9UZ1 の概要

• エントリーDOI: 10.2210/pdb9uz1/pdb
• 関連するBIRD辞書のPRD_ID: PRD_900001
• 分子名称: Maltose/maltodextrin-binding periplasmic protein,Indoleamine 2,3-dioxygenase 2, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, TRYPTOPHAN, ... (10 entities in total)
• 機能のキーワード: hem protein, mutant, complex, oxidoreductase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 88485.28

構造登録者

Takahashi, A.,Inoue, T.,Fukuda, Y.,Adachi, N. (登録日: 2025-05-16, 公開日: 2026-04-08)

主引用文献

Nogi, S.,Takahashi, A.,Murakami, S.,Adachi, N.,Fujimoto, T.,Fukuda, Y.,Yamashita, T.,Inoue, T.,Tsujino, H.
Human IDO2 exhibits unique binding affinities distinct to those of human IDO1.
Febs J., 2026

PubMed Abstract: Indoleamine 2,3-dioxygenase 2 (IDO2) is a heme enzyme in the kynurenine pathway that shares high structural similarity with IDO1 but exhibits markedly lower catalytic activity. To clarify the molecular basis of this difference, we performed spectroscopic, biochemical, and crystallographic analyses of human IDO2. We found that IDO2 binds L-tryptophan (L-Trp) in a flipped orientation stabilized by the IDO2-specific residue His143, which results in inefficient catalysis. Replacement of His143 with tyrosine, the corresponding residue in IDO1, restored an IDO1-like binding mode of L-Trp and enhanced activity by more than 1000-fold. Structural analyses further revealed that IDO2 accommodates various tryptophan derivatives, such as 5-methyl-l-Trp (5MT) and 5-methoxy-l-Trp (5MoT), in a productive conformation, while other ligands, including D-Trp and serotonin, adopt nonproductive poses. In addition, we observed that 5MT and 5MoT are metabolized by IDO2 at levels comparable to the metabolism of L-Trp by human tryptophan 2,3-dioxygenase. These results highlight the unique structural constraints that underlie IDO2's low activity and broadened substrate recognition, providing a molecular framework for understanding the functional divergence between IDO1 and IDO2.

PubMed: 41804238
DOI: 10.1111/febs.70476

実験手法

X-RAY DIFFRACTION (2.35 Å)