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To clarify the molecular basis of this difference, we performed spectroscopic, biochemical, and crystallographic analyses of human IDO2. We found that IDO2 binds L\u2010tryptophan (L\u2010Trp) in a flipped orientation stabilized by the IDO2\u2010specific residue His143, which results in inefficient catalysis. Replacement of His143 with tyrosine, the corresponding residue in IDO1, restored an IDO1\u2010like binding mode of L\u2010Trp and enhanced activity by more than 1000\u2010fold. Structural analyses further revealed that IDO2 accommodates various tryptophan derivatives, such as 5\u2010methyl\u2010\n                    <jats:sc>l<\/jats:sc>\n                    \u2010Trp (5MT) and 5\u2010methoxy\u2010\n                    <jats:sc>l<\/jats:sc>\n                    \u2010Trp (5MoT), in a productive conformation, while other ligands, including D\u2010Trp 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\u2010Trp by human tryptophan 2,3\u2010dioxygenase. 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.\n                  <\/jats:p>","DOI":"10.1111\/febs.70476","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T07:06:17Z","timestamp":1773126377000},"page":"4533-4553","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Human\n                    <scp>IDO2<\/scp>\n                    exhibits unique binding affinities distinct to those of human\n                    <scp>IDO1<\/scp>"],"prefix":"10.1111","volume":"293","author":[{"given":"Shunsuke","family":"Nogi","sequence":"first","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences The University of Osaka  Suita 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