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==Mapping the binding trajectory of a suicide inhibitor in human indoleamine 2,3-dioxygenase 1== | |||
<StructureSection load='6dpr' size='340' side='right' caption='[[6dpr]], [[Resolution|resolution]] 3.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6dpr]] is a 2 chain structure. 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> | |||
</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> | |||
<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='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> | |||
== 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> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:30347977</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Yeh, S | <div class="pdbe-citations 6dpr" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Indoleamine 2,3-dioxygenase]] | |||
[[Category: Pham, K N]] | |||
[[Category: Yeh, S R]] | |||
[[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]] | |||
Revision as of 15:14, 7 November 2018
Mapping the binding trajectory of a suicide inhibitor in human indoleamine 2,3-dioxygenase 1Mapping the binding trajectory of a suicide inhibitor in human indoleamine 2,3-dioxygenase 1
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 PubMedHuman 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. References
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