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| | <StructureSection load='6dpr' size='340' side='right'caption='[[6dpr]], [[Resolution|resolution]] 3.20Å' scene=''> | | <StructureSection load='6dpr' size='340' side='right'caption='[[6dpr]], [[Resolution|resolution]] 3.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6dpr]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DPR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DPR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6dpr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DPR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DPR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=H7P:(2R)-N-(4-chlorophenyl)-2-[cis-4-(6-fluoroquinolin-4-yl)cyclohexyl]propanamide'>H7P</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6dpq|6dpq]], [[5wmu|5wmu]], [[5wmv|5wmv]], [[5wmw|5wmw]], [[5wmx|5wmx]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=H7P:(2R)-N-(4-chlorophenyl)-2-[cis-4-(6-fluoroquinolin-4-yl)cyclohexyl]propanamide'>H7P</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IDO1, IDO, INDO ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6dpr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dpr OCA], [https://pdbe.org/6dpr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dpr RCSB], [https://www.ebi.ac.uk/pdbsum/6dpr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dpr ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase Indoleamine 2,3-dioxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.13.11.52 1.13.11.52] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6dpr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dpr OCA], [http://pdbe.org/6dpr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dpr RCSB], [http://www.ebi.ac.uk/pdbsum/6dpr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dpr ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/I23O1_HUMAN I23O1_HUMAN]] Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.<ref>PMID:17671174</ref> | + | [https://www.uniprot.org/uniprot/I23O1_HUMAN I23O1_HUMAN] Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.<ref>PMID:17671174</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Indoleamine 2,3-dioxygenase]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Pham, K N]] | + | [[Category: Pham KN]] |
| - | [[Category: Yeh, S R]] | + | [[Category: Yeh SR]] |
| - | [[Category: 3-dioxygenase]]
| + | |
| - | [[Category: Bms-986205]]
| + | |
| - | [[Category: Heme-containing enzyme]]
| + | |
| - | [[Category: Hido1-selective inhibitor]]
| + | |
| - | [[Category: Indoleamine 2]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: Structure-based design]]
| + | |
| Structural highlights
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 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.
Mapping the Binding Trajectory of a Suicide Inhibitor in Human Indoleamine 2,3-Dioxygenase 1.,Pham KN, Yeh SR J Am Chem Soc. 2018 Oct 24. doi: 10.1021/jacs.8b07994. PMID:30347977[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
- ↑ Pham KN, Yeh SR. Mapping the Binding Trajectory of a Suicide Inhibitor in Human Indoleamine 2,3-Dioxygenase 1. J Am Chem Soc. 2018 Oct 24. doi: 10.1021/jacs.8b07994. PMID:30347977 doi:http://dx.doi.org/10.1021/jacs.8b07994
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