{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T23:10:25Z","timestamp":1792019425141,"version":"4.4.0"},"reference-count":33,"publisher":"National Academy of Sciences","issue":"8","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,2,21]]},"abstract":"<jats:p>\n                    Human indoleamine 2,3-dioxygenase (IDO) catalyzes the cleavage of the pyrrol ring of\n                    <jats:sc>l<\/jats:sc>\n                    -Trp and incorporates both atoms of a molecule of oxygen (O\n                    <jats:sub>2<\/jats:sub>\n                    ). Here we report on the x-ray crystal structure of human IDO, complexed with the ligand inhibitor 4-phenylimidazole and cyanide. The overall structure of IDO shows two \u03b1-helical domains with the heme between them. A264 of the flexible loop in the heme distal side is in close proximity to the iron. A mutant analysis shows that none of the polar amino acid residues in the distal heme pocket are essential for activity, suggesting that, unlike the heme-containing monooxygenases (i.e., peroxidase and cytochrome P450), no protein group of IDO is essential in dioxygen activation or proton abstraction. These characteristics of the IDO structure provide support for a reaction mechanism involving the abstraction of a proton from the substrate by iron-bound dioxygen. Inactive mutants (F226A, F227A, and R231A) retain substrate-binding affinity, and an electron density map reveals that 2-(\n                    <jats:italic>N<\/jats:italic>\n                    -cyclohexylamino)ethane sulfonic acid is bound to these residues, mimicking the substrate. These findings suggest that strict shape complementarities between the indole ring of the substrate and the protein side chains are required, not for binding, but, rather, to permit the interaction between the substrate and iron-bound dioxygen in the first step of the reaction. This study provides the structural basis for a heme-containing dioxygenase mechanism, a missing piece in our understanding of heme chemistry.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0508996103","type":"journal-article","created":{"date-parts":[[2006,2,13]],"date-time":"2006-02-13T20:44:07Z","timestamp":1139863447000},"page":"2611-2616","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":412,"title":["Crystal structure of human indoleamine 2,3-dioxygenase: Catalytic mechanism of O\n                    <sub>2<\/sub>\n                    incorporation by a heme-containing dioxygenase"],"prefix":"10.1073","volume":"103","author":[{"given":"Hiroshi","family":"Sugimoto","sequence":"first","affiliation":[{"name":"*Biometal Science Laboratory, RIKEN SPring-8 Center, Harima Institute, Hyogo 679-5148, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun-ichiro","family":"Oda","sequence":"additional","affiliation":[{"name":"*Biometal Science Laboratory, RIKEN SPring-8 Center, Harima Institute, Hyogo 679-5148, Japan;"},{"name":"Department of Life Science, Graduate School of Science, Himeji Institute of Technology, Hyogo 678-1297, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Otsuki","sequence":"additional","affiliation":[{"name":"*Biometal Science Laboratory, RIKEN SPring-8 Center, Harima Institute, Hyogo 679-5148, Japan;"},{"name":"Department of Life Science, Graduate School of Science, Himeji Institute of Technology, Hyogo 678-1297, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Hino","sequence":"additional","affiliation":[{"name":"*Biometal Science Laboratory, RIKEN SPring-8 Center, Harima Institute, Hyogo 679-5148, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Yamagata University School of Medicine, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitsugu","family":"Shiro","sequence":"additional","affiliation":[{"name":"*Biometal Science Laboratory, RIKEN SPring-8 Center, Harima Institute, Hyogo 679-5148, Japan;"},{"name":"Department of Life Science, Graduate School of Science, Himeji Institute of Technology, Hyogo 678-1297, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2006,2,13]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1126\/science.164.3878.389","volume":"164","author":"Hayaishi O.","year":"1969","unstructured":"O. Hayaishi, M. Nozaki Science 164, 389\u2013396 (1969).","journal-title":"Science"},{"key":"e_1_3_3_2_2","doi-asserted-by":"crossref","first-page":"5260","DOI":"10.1016\/S0021-9258(18)99420-2","volume":"242","author":"Yamamoto S.","year":"1967","unstructured":"S. Yamamoto, O. Hayaishi J. Biol. Chem 242, 5260\u20135266 (1967).","journal-title":"J. Biol. Chem"},{"key":"e_1_3_3_3_2","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S0021-9258(19)63693-8","volume":"229","author":"Hayaishi O.","year":"1957","unstructured":"O. Hayaishi, S. Rothberg, A. H. Mehler, Y. Saito J. Biol. Chem 229, 889\u2013896 (1957).","journal-title":"J. Biol. Chem"},{"key":"e_1_3_3_4_2","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/S0021-9258(19)50967-X","volume":"187","author":"Knox W. E.","year":"1950","unstructured":"W. E. Knox, A. H. Mehler J. Biol. Chem 187, 419\u2013430 (1950).","journal-title":"J. Biol. Chem"},{"key":"e_1_3_3_5_2","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/978-1-4615-0135-0_31","volume":"527","author":"Takikawa O.","year":"2003","unstructured":"O. Takikawa, R. J. Truscott, M. Fukao, S. Miwa Adv. Exp. Med. Biol 527, 277\u2013285 (2003).","journal-title":"Adv. Exp. Med. Biol"},{"key":"e_1_3_3_6_2","doi-asserted-by":"crossref","first-page":"4700","DOI":"10.1016\/S0021-9258(17)30447-7","volume":"253","author":"Shimizu T.","year":"1978","unstructured":"T. Shimizu, S. Nomiyama, F. Hirata, O. Hayaishi J. Biol. Chem 253, 4700\u20134706 (1978).","journal-title":"J. Biol. Chem"},{"key":"e_1_3_3_7_2","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1038\/nri1457","volume":"4","author":"Mellor A. L.","year":"2004","unstructured":"A. L. Mellor, D. H. Munn Nat. Rev. Immunol 4, 762\u2013774 (2004).","journal-title":"Nat. Rev. Immunol"},{"key":"e_1_3_3_8_2","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1021\/ja003583l","volume":"123","author":"Davydov R.","year":"2001","unstructured":"R. Davydov, T. M. Makris, V. Kofman, D. E. Werst, S. G. Sligar, B. M. Hoffman J. Am. Chem. Soc 123, 1403\u20131415 (2001).","journal-title":"J. Am. Chem. Soc"},{"key":"e_1_3_3_9_2","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1126\/science.287.5458.1615","volume":"287","author":"Schlichting I.","year":"2000","unstructured":"I. Schlichting, J. Berendzen, K. Chu, A. M. Stock, S. A. Maves, D. E. Benson, R. M. Sweet, D. Ringe, G. A. Petsko, S. G. Sligar Science 287, 1615\u20131622 (2000).","journal-title":"Science"},{"key":"e_1_3_3_10_2","doi-asserted-by":"crossref","first-page":"5714","DOI":"10.1021\/bi00440a003","volume":"28","author":"Baek H. K.","year":"1989","unstructured":"H. K. Baek, H. E. Van Wart Biochemistry 28, 5714\u20135719 (1989).","journal-title":"Biochemistry"},{"key":"e_1_3_3_11_2","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1021\/cr9500500","volume":"96","author":"Sono M.","year":"1996","unstructured":"M. Sono, M. P. Roach, E. D. Coulter, J. H. Dawson Chem. Rev 96, 2841\u20132888 (1996).","journal-title":"Chem. Rev"},{"key":"e_1_3_3_12_2","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1126\/science.1078020","volume":"299","author":"Karlsson A.","year":"2003","unstructured":"A. Karlsson, J. V. Parales, R. E. Parales, D. T. Gibson, H. Eklund, S. Ramaswamy Science 299, 1039\u20131042 (2003).","journal-title":"Science"},{"key":"e_1_3_3_13_2","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1006\/jmbi.1996.0060","volume":"255","author":"Senda T.","year":"1996","unstructured":"T. Senda, K. Sugiyama, H. Narita, T. Yamamoto, K. Kimbara, M. Fukuda, M. Sato, K. Yano, Y. Mitsui J. Mol. Biol 255, 735\u2013752 (1996).","journal-title":"J. Mol. Biol"},{"key":"e_1_3_3_14_2","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1021\/bi00458a016","volume":"29","author":"Sono M.","year":"1990","unstructured":"M. Sono Biochemistry 29, 1451\u20131460 (1990).","journal-title":"Biochemistry"},{"key":"e_1_3_3_15_2","first-page":"3600","volume":"22","author":"Holm L.","year":"1994","unstructured":"L. Holm, C. Sander Nucleic Acids Res 22, 3600\u20133609 (1994).","journal-title":"Nucleic Acids Res"},{"key":"e_1_3_3_16_2","doi-asserted-by":"crossref","first-page":"29525","DOI":"10.1074\/jbc.M301700200","volume":"278","author":"Littlejohn T. K.","year":"2003","unstructured":"T. K. Littlejohn, O. Takikawa, R. J. Truscott, M. J. Walker J. Biol. Chem 278, 29525\u201329531 (2003).","journal-title":"J. Biol. Chem"},{"key":"e_1_3_3_17_2","doi-asserted-by":"crossref","first-page":"15788","DOI":"10.1074\/jbc.M200457200","volume":"277","author":"Terentis A. C.","year":"2002","unstructured":"A. C. Terentis, S. R. Thomas, O. Takikawa, T. K. Littlejohn, R. J. Truscott, R. S. Armstrong, S. R. Yeh, R. Stocker J. Biol. Chem 277, 15788\u201315794 (2002).","journal-title":"J. Biol. Chem"},{"key":"e_1_3_3_18_2","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/0167-4838(84)90202-4","volume":"789","author":"Sono M.","year":"1984","unstructured":"M. Sono, J. H. Dawson Biochim. Biophys. Acta 789, 170\u2013187 (1984).","journal-title":"Biochim. Biophys. Acta"},{"key":"e_1_3_3_19_2","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1074\/jbc.275.3.1679","volume":"275","author":"Yeh S. R.","year":"2000","unstructured":"S. R. Yeh, M. Couture, Y. Ouellet, M. Guertin, D. L. Rousseau J. Biol. Chem 275, 1679\u20131684 (2000).","journal-title":"J. Biol. Chem"},{"key":"e_1_3_3_20_2","first-page":"559","volume-title":"Molecular Mechanisms of Oxygen Activation","author":"Gunsalus I. C.","year":"1974","unstructured":"I. C. Gunsalus, J. R. Meek, J. D. Lipscomb, P. Debrunner, E. Munk Molecular Mechanisms of Oxygen Activation, ed O. Hayashi (Academic, New York), pp. 559\u2013613 (1974)."},{"key":"e_1_3_3_21_2","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1146\/annurev.bi.49.070180.001531","volume":"49","author":"White R. E.","year":"1980","unstructured":"R. E. White, M. J. Coon Annu. Rev. Biochem 49, 315\u2013356 (1980).","journal-title":"Annu. Rev. Biochem"},{"key":"e_1_3_3_22_2","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1073\/pnas.96.5.1863","volume":"96","author":"Sevrioukova I. F.","year":"1999","unstructured":"I. F. Sevrioukova, H. Li, H. Zhang, J. A. Peterson, T. L. Poulos Proc. Natl. Acad. Sci. USA 96, 1863\u20131868 (1999).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_3_3_23_2","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1126\/science.270.5238.976","volume":"270","author":"Han S.","year":"1995","unstructured":"S. Han, L. D. Eltis, K. N. Timmis, S. W. Muchmore, J. T. Bolin Science 270, 976\u2013980 (1995).","journal-title":"Science"},{"key":"e_1_3_3_24_2","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0925-4439(99)00096-4","volume":"1500","author":"Kudo Y.","year":"2000","unstructured":"Y. Kudo, C. A. Boyd Biochim. Biophys. Acta 1500, 119\u2013124 (2000).","journal-title":"Biochim. Biophys. Acta"},{"key":"e_1_3_3_25_2","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/S0076-6879(97)76073-7","volume":"276","author":"Fortelle E. D. L.","year":"1997","unstructured":"E. D. L. Fortelle, G. Bricogne Methods Enzymol 276, 472\u2013494 (1997).","journal-title":"Methods Enzymol"},{"key":"e_1_3_3_26_2","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0076-6879(97)77016-2","volume":"277","author":"Lamzin V. S.","year":"1997","unstructured":"V. S. Lamzin, K. S. Wilson Methods Enzymol 277, 269\u2013305 (1997).","journal-title":"Methods Enzymol"},{"key":"e_1_3_3_27_2","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1107\/S0108767390010224","volume":"47","author":"Jones T. A.","year":"1991","unstructured":"T. A. Jones, J. Y. Zou, S. W. Cowan, M. Kjeldgaard Acta Crystallogr. A 47, 110\u2013119 (1991).","journal-title":"Acta Crystallogr. A"},{"key":"e_1_3_3_28_2","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1107\/S0907444998003254","volume":"54","author":"Brunger A. T.","year":"1998","unstructured":"A. T. Brunger, P. D. Adams, G. M. Clore, W. L. DeLano, P. Gros, R. W. Grosse-Kunstleve, J. S. Jiang, J. Kuszewski, M. Nilges, N. S. Pannu, et al. Acta Crystallogr. D 54, 905\u2013921 (1998).","journal-title":"Acta Crystallogr. D"},{"key":"e_1_3_3_29_2","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1107\/S0021889891004399","volume":"24","author":"Kraulis P. J.","year":"1991","unstructured":"P. J. Kraulis J. Appl. Crystallogr 24, 946\u2013950 (1991).","journal-title":"J. Appl. Crystallogr"},{"key":"e_1_3_3_30_2","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S0076-6879(97)77028-9","volume":"277","author":"Merritt E. A.","year":"1997","unstructured":"E. A. Merritt, D. J. Bacon Methods Enzymol 277, 505\u2013524 (1997).","journal-title":"Methods Enzymol"},{"key":"e_1_3_3_31_2","volume-title":"The pymol Molecular Graphics System","author":"DeLano W. L.","year":"2002","unstructured":"W. L. DeLano The pymol Molecular Graphics System (DeLano Scientific, San Carlos, CA, 2002)."},{"key":"e_1_3_3_32_2","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/prot.340110407","volume":"11","author":"Nicholls A.","year":"1991","unstructured":"A. Nicholls, K. A. Sharp, B. Honig Proteins 11, 281\u2013296 (1991).","journal-title":"Proteins"},{"key":"e_1_3_3_33_2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.bbagen.2005.03.010","volume":"1724","author":"Dobrovolsky V. N.","year":"2005","unstructured":"V. N. Dobrovolsky, J. F. Bowyer, M. K. Pabarcus, R. H. Heflich, L. D. Williams, D. R. Doerge, B. Arvidsson, J. Bergquist, J. E. Casida Biochim. Biophys. Acta 1724, 163\u2013172 (2005).","journal-title":"Biochim. Biophys. Acta"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0508996103","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T02:18:39Z","timestamp":1654568319000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0508996103"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,2,13]]},"references-count":33,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2006,2,21]]}},"alternative-id":["10.1073\/pnas.0508996103"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0508996103","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,2,13]]},"assertion":[{"value":"2005-10-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2006-02-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}