6DPR
Mapping the binding trajectory of a suicide inhibitor in human indoleamine 2,3-dioxygenase 1
Summary for 6DPR
| Entry DOI | 10.2210/pdb6dpr/pdb |
| Related | 5WMU 5WMV 5WMW 5WMX 5WN8 6DPQ |
| Descriptor | Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, (2R)-N-(4-chlorophenyl)-2-[cis-4-(6-fluoroquinolin-4-yl)cyclohexyl]propanamide, ... (5 entities in total) |
| Functional Keywords | indoleamine 2, 3-dioxygenase, heme-containing enzyme, bms-986205, structure-based design, hido1-selective inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 97220.40 |
| Authors | Pham, K.N.,Yeh, S.R. (deposition date: 2018-06-09, release date: 2018-11-07, Last modification date: 2024-11-13) |
| Primary citation | Pham, K.N.,Yeh, S.R. Mapping the Binding Trajectory of a Suicide Inhibitor in Human Indoleamine 2,3-Dioxygenase 1. J. Am. Chem. Soc., 140:14538-14541, 2018 Cited by PubMed Abstract: Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an important heme-containing enzyme that is a key drug target for cancer immunotherapy. Several hIDO1 inhibitors have entered clinical trials, among which BMS-986205 (BMS) stands out as the only suicide inhibitor. Despite its "best-in-class" activity, the action mechanism of BMS remains elusive. Here, we report three crystal structures of hIDO1-BMS complexes that define the complete binding trajectory of the inhibitor. BMS first binds in a solvent exposed surface cleft near the active site in an extended conformation. The initial binding partially unfolds the active site, which triggers heme release, thereby exposing a new binding pocket. The inhibitor then undergoes a large scale movement to this new binding pocket, where it binds by adopting a high energy kinked conformation. Finally, the inhibitor relaxes to a bent conformation, via an additional large scale rearrangement, culminating in the energy minimum state. The structural data offer a molecular explanation for the remarkable efficacy and suicide inhibition activity of the inhibitor. They also suggest a novel strategy that can be applied for drug development targeting hIDO1 and related enzymes. PubMed: 30347977DOI: 10.1021/jacs.8b07994 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.2 Å) |
Structure validation
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