| Structural highlights
5wmx is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , |
| Related: | 5wmu, 5wmv, 5wmw |
| Gene: | IDO1, IDO, INDO (HUMAN) |
| Activity: | Indoleamine 2,3-dioxygenase, with EC number 1.13.11.52 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[I23O1_HUMAN] Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.[1]
Publication Abstract from PubMed
Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape. However, drug development has been hindered by limited structural information. Here, we report the crystal structures of hIDO1 in complex with its substrate, Trp, an inhibitor, epacadostat, and/or an effector, indole ethanol (IDE). The data reveal structural features of the active site (Sa) critical for substrate activation; in addition, they disclose a new inhibitor-binding mode and a distinct small molecule binding site (Si). Structure-guided mutation of a critical residue, F270, to glycine perturbs the Si site, allowing structural determination of an inhibitory complex, where both the Sa and Si sites are occupied by Trp. The Si site offers a novel target site for allosteric inhibitors and a molecular explanation for the previously baffling substrate-inhibition behavior of the enzyme. Taken together, the data open exciting new avenues for structure-based drug design.
Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1.,Lewis-Ballester A, Pham KN, Batabyal D, Karkashon S, Bonanno JB, Poulos TL, Yeh SR Nat Commun. 2017 Nov 22;8(1):1693. doi: 10.1038/s41467-017-01725-8. PMID:29167421[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res. 2007 Aug 1;67(15):7082-7. PMID:17671174 doi:http://dx.doi.org/10.1158/0008-5472.CAN-07-1872
- ↑ Lewis-Ballester A, Pham KN, Batabyal D, Karkashon S, Bonanno JB, Poulos TL, Yeh SR. Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1. Nat Commun. 2017 Nov 22;8(1):1693. doi: 10.1038/s41467-017-01725-8. PMID:29167421 doi:http://dx.doi.org/10.1038/s41467-017-01725-8
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