5WMW
Structural Insights into Substrate and Inhibitor Binding Sites in Human Indoleamine 2,3-Dioxygenase 1
Summary for 5WMW
| Entry DOI | 10.2210/pdb5wmw/pdb |
| Descriptor | Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, CYANIDE ION, ... (5 entities in total) |
| Functional Keywords | dioxygenase tryptophan heme inhibitor, oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 97505.50 |
| Authors | Lewis-Ballester, A.,Yeh, S.R.,Pham, K.N.,Batabyal, D.,Karkashon, S.,Bonanno, J.B.,Poulos, T.L. (deposition date: 2017-07-31, release date: 2017-12-06, Last modification date: 2024-10-16) |
| Primary citation | Lewis-Ballester, A.,Pham, K.N.,Batabyal, D.,Karkashon, S.,Bonanno, J.B.,Poulos, T.L.,Yeh, S.R. Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1. Nat Commun, 8:1693-1693, 2017 Cited by PubMed Abstract: 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. PubMed: 29167421DOI: 10.1038/s41467-017-01725-8 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.03 Å) |
Structure validation
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