6dpq: Difference between revisions
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<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> | <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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.94Å</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]] 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:( | <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'>[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> | ||
</table> | </table> | ||
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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