5wn8: Difference between revisions
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==Structural Insights into Substrate and Inhibitor Binding Sites in Human Indoleamine 2,3-Dioxygenase 1== | |||
<StructureSection load='5wn8' size='340' side='right'caption='[[5wn8]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5wn8]] 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=5WN8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WN8 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]] 2.5Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BBJ:N-(3-bromo-4-fluorophenyl)-N-hydroxy-4-{[2-(sulfamoylamino)ethyl]amino}-1,2,5-oxadiazole-3-carboximidamide'>BBJ</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=5wn8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wn8 OCA], [https://pdbe.org/5wn8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wn8 RCSB], [https://www.ebi.ac.uk/pdbsum/5wn8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wn8 ProSAT]</span></td></tr> | |||
</table> | |||
== 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;"> | |||
== Publication Abstract from PubMed == | |||
Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape. However, drug development has been hindered by limited structural information. Here, we report the crystal structures of hIDO1 in complex with its substrate, Trp, an inhibitor, epacadostat, and/or an effector, indole ethanol (IDE). The data reveal structural features of the active site (Sa) critical for substrate activation; in addition, they disclose a new inhibitor-binding mode and a distinct small molecule binding site (Si). Structure-guided mutation of a critical residue, F270, to glycine perturbs the Si site, allowing structural determination of an inhibitory complex, where both the Sa and Si sites are occupied by Trp. The Si site offers a novel target site for allosteric inhibitors and a molecular explanation for the previously baffling substrate-inhibition behavior of the enzyme. Taken together, the data open exciting new avenues for structure-based drug design. | |||
Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1.,Lewis-Ballester A, Pham KN, Batabyal D, Karkashon S, Bonanno JB, Poulos TL, Yeh SR Nat Commun. 2017 Nov 22;8(1):1693. doi: 10.1038/s41467-017-01725-8. PMID:29167421<ref>PMID:29167421</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5wn8" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: Karkashon | *[[Dioxygenase 3D structures|Dioxygenase 3D structures]] | ||
[[Category: | == References == | ||
[[Category: Pham | <references/> | ||
[[Category: | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Batabyal D]] | |||
[[Category: Bonanno JB]] | |||
[[Category: Karkashon S]] | |||
[[Category: Lewis-Ballester A]] | |||
[[Category: Pham KN]] | |||
[[Category: Poulos TL]] | |||
[[Category: Yeh SR]] | |||
Latest revision as of 17:17, 4 October 2023
Structural Insights into Substrate and Inhibitor Binding Sites in Human Indoleamine 2,3-Dioxygenase 1Structural Insights into Substrate and Inhibitor Binding Sites 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 attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape. However, drug development has been hindered by limited structural information. Here, we report the crystal structures of hIDO1 in complex with its substrate, Trp, an inhibitor, epacadostat, and/or an effector, indole ethanol (IDE). The data reveal structural features of the active site (Sa) critical for substrate activation; in addition, they disclose a new inhibitor-binding mode and a distinct small molecule binding site (Si). Structure-guided mutation of a critical residue, F270, to glycine perturbs the Si site, allowing structural determination of an inhibitory complex, where both the Sa and Si sites are occupied by Trp. The Si site offers a novel target site for allosteric inhibitors and a molecular explanation for the previously baffling substrate-inhibition behavior of the enzyme. Taken together, the data open exciting new avenues for structure-based drug design. Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1.,Lewis-Ballester A, Pham KN, Batabyal D, Karkashon S, Bonanno JB, Poulos TL, Yeh SR Nat Commun. 2017 Nov 22;8(1):1693. doi: 10.1038/s41467-017-01725-8. PMID:29167421[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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