21om

Crystal structure of the indoleamine 2,3-dioxygenagse 2 (IDO2) complexed with 5-hydroxy-L-Trp

spinqualitylabelsall models 21om, resolution 2.68Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 21om is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.68Å Ligands: 4PQ, CYN, EDO, GLC, HEM, NA, PRD_900001 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Human IDO2 exhibits unique binding affinities distinct to those of human IDO1.,Nogi S, Takahashi A, Murakami S, Adachi N, Fujimoto T, Fukuda Y, Yamashita T, Inoue T, Tsujino H FEBS J. 2026 Mar 10. doi: 10.1111/febs.70476. PMID:41804238 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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