6dpq: Difference between revisions
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==Mapping the binding trajectory of a suicide inhibitor in human indoleamine 2,3-dioxygenase 1== | ==Mapping the binding trajectory of a suicide inhibitor in human indoleamine 2,3-dioxygenase 1== | ||
<StructureSection load='6dpq' size='340' side='right' caption='[[6dpq]], [[Resolution|resolution]] 2.94Å' scene=''> | <StructureSection load='6dpq' size='340' side='right'caption='[[6dpq]], [[Resolution|resolution]] 2.94Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6dpq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DPQ OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6dpq]] 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=6DPQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DPQ FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=H7P:( | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.94Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=H7P:(2~{R})-~{N}-(4-chlorophenyl)-2-[4-(6-fluoranylquinolin-4-yl)cyclohexyl]propanamide'>H7P</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></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=6dpq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dpq OCA], [https://pdbe.org/6dpq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dpq RCSB], [https://www.ebi.ac.uk/pdbsum/6dpq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dpq ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [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 == | ||
| Line 20: | Line 19: | ||
</div> | </div> | ||
<div class="pdbe-citations 6dpq" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6dpq" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Dioxygenase 3D structures|Dioxygenase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Pham KN]] | ||
[[Category: | [[Category: Yeh SR]] | ||
Latest revision as of 15:33, 6 November 2024
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
FunctionI23O1_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. See AlsoReferences
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