2D0T

Crystal structure of 4-phenylimidazole bound form of human indoleamine 2,3-dioxygenase

Summary for 2D0T

• Entry DOI: 10.2210/pdb2d0t/pdb
• Related: 2D0U
• Descriptor: Indoleamine 2,3-dioxygenase, PROTOPORPHYRIN IX CONTAINING FE, 4-PHENYL-1H-IMIDAZOLE, ... (5 entities in total)
• Functional Keywords: helix bundle, riken structural genomics/proteomics initiative, rsgi, structural genomics, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 93683.44

Authors

Sugimoto, H.,Oda, S.,Otsuki, T.,Hino, T.,Yoshida, T.,Shiro, Y.,RIKEN Structural Genomics/Proteomics Initiative (RSGI) (deposition date: 2005-08-08, release date: 2006-01-31, Last modification date: 2024-10-30)

Primary citation

Sugimoto, H.,Oda, S.,Otsuki, T.,Hino, T.,Yoshida, T.,Shiro, Y.
Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase.
Proc.Natl.Acad.Sci.Usa, 103:2611-2616, 2006

PubMed Abstract: Human indoleamine 2,3-dioxygenase (IDO) catalyzes the cleavage of the pyrrol ring of L-Trp and incorporates both atoms of a molecule of oxygen (O2). 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 alpha-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-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.

PubMed: 16477023
DOI: 10.1073/pnas.0508996103

Experimental method

X-RAY DIFFRACTION (2.3 Å)