PDBsum entry 2d0t

Oxidoreductase

PDB id: 2d0t

Contents

Protein chain

373 a.a. *

Ligands

HEM-PIM ×2

NHE ×4

Waters ×138

* Residue conservation analysis

PDB id:

2d0t

Name:

Oxidoreductase

Title:

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

Structure:

Indoleamine 2,3-dioxygenase. Chain: a, b. Synonym: ido, indoleamine-pyrrole 2,3-dioxygenase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.30Å R-factor: 0.191 R-free: 0.221

Authors:

H.Sugimoto,S.Oda,T.Otsuki,T.Hino,T.Yoshida,Y.Shiro,Riken Structural Genomics/proteomics Initiative (Rsgi)

Key ref:

H.Sugimoto et al. (2006). Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. Proc Natl Acad Sci U S A, 103, 2611-2616. PubMed id: 16477023 DOI: 10.1073/pnas.0508996103

Date:

08-Aug-05 Release date: 31-Jan-06

Protein chains

P14902  (I23O1_HUMAN) -  Indoleamine 2,3-dioxygenase 1 from Homo sapiens

Seq: 403 a.a.

Struc: 373 a.a.

Enzyme reactions

• Enzyme class: E.C.1.13.11.52 - indoleamine 2,3-dioxygenase.
• Reaction:
  1. D-tryptophan + O2 = N-formyl-D-kynurenine
  2. L-tryptophan + O2 = N-formyl-L-kynurenine

D-tryptophan (Bound ligand (Het Group name = PIM) matches with 62.50% similarity) + O2 = N-formyl-D-kynurenine

L-tryptophan (Bound ligand (Het Group name = PIM) matches with 62.50% similarity) + O2 = N-formyl-L-kynurenine

• Cofactor: Heme

Heme (Bound ligand (Het Group name = HEM) matches with 95.45% similarity)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1073/pnas.0508996103

Proc Natl Acad Sci U S A 103:2611-2616 (2006)

PubMed id: 16477023

Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase.

H.Sugimoto, S.Oda, T.Otsuki, T.Hino, T.Yoshida, Y.Shiro.

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.

Selected figure(s)

Figure 1.
Fig. 1. Structure of IDO–PI complex. (A) Ribbon representation of the overall structure of human IDO. The small and large domains are represented by blue and green ribbons, respectively. The helices A–S are named in the order of appearance in the primary sequence. The connecting helices (K-L and N) are colored in cyan. The long loop connecting the two domains is colored in red. The heme (yellow), proximal ligand H346 (white), and heme inhibitor 4-phynylimidazole (white) are shown in a ball-and-stick model. The helices of the large domain create the cavity for the heme. The connecting loop (red) and small domain above the sixth-coordination site (heme distal side) cover the top of cavity on the heme. (B) The four proximal helices I, G, Q, and S run in parallel. The helices N (blue) and K-L (cyan) connect the two domains. The connecting loop (red) and small domain above the sixth-coordination site of the heme cover the top of the cavity on the heme.

Figure 3.
Fig. 3. Active site of IDO–PI complex. (A) Stereoview of the residues around the heme of IDO viewed from the side of heme plane. The proximal ligand H346 is H-bonded to wa1. The 6-propionate of the heme contacts with wa2 and R343 N . The wa2 is H-bonded to wa1, L388 O, and 6-propionate. Mutations of F226, F227, and R231 do not lose the substrate affinity but produce the inactive enzyme. Two CHES molecules are bound in the distal pocket. The cyclohexan ring of CHES-1 (green) contacts with F226 and R231. The 7-propionate of the heme interacts with the amino group of CHES-1 and side chain of Ser-263. The mutational analyses for these distal residues are shown in Table 1. (B) Top view of A by a rotation of 90°. The proximal residues are omitted.

Figures were selected by the author.