7ah5: Difference between revisions
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==Crystal structure of indoleamine 2,3-dioxygenase 1 (IDO1) in complex with ferric heme and MMG-0706== | ==Crystal structure of indoleamine 2,3-dioxygenase 1 (IDO1) in complex with ferric heme and MMG-0706== | ||
<StructureSection load='7ah5' size='340' side='right'caption='[[7ah5]]' scene=''> | <StructureSection load='7ah5' size='340' side='right'caption='[[7ah5]], [[Resolution|resolution]] 2.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AH5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AH5 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7ah5]] 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=7AH5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AH5 FirstGlance]. <br> | ||
</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=7ah5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ah5 OCA], [https://pdbe.org/7ah5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ah5 RCSB], [https://www.ebi.ac.uk/pdbsum/7ah5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ah5 ProSAT]</span></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]] 2.9Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=RCQ:4-chloranyl-2-(1~{H}-1,2,4-triazol-5-yl)aniline'>RCQ</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=7ah5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ah5 OCA], [https://pdbe.org/7ah5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ah5 RCSB], [https://www.ebi.ac.uk/pdbsum/7ah5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ah5 ProSAT]</span></td></tr> | |||
</table> | </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 == | |||
The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme-ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds. | |||
Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.,Rohrig UF, Majjigapu SR, Reynaud A, Pojer F, Dilek N, Reichenbach P, Ascencao K, Irving M, Coukos G, Vogel P, Michielin O, Zoete V J Med Chem. 2021 Feb 25;64(4):2205-2227. doi: 10.1021/acs.jmedchem.0c01968. Epub , 2021 Feb 8. PMID:33557523<ref>PMID:33557523</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7ah5" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Dioxygenase 3D structures|Dioxygenase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Michielin O]] | [[Category: Michielin O]] | ||
Revision as of 15:09, 1 February 2024
Crystal structure of indoleamine 2,3-dioxygenase 1 (IDO1) in complex with ferric heme and MMG-0706Crystal structure of indoleamine 2,3-dioxygenase 1 (IDO1) in complex with ferric heme and MMG-0706
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 PubMedThe heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme-ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds. Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.,Rohrig UF, Majjigapu SR, Reynaud A, Pojer F, Dilek N, Reichenbach P, Ascencao K, Irving M, Coukos G, Vogel P, Michielin O, Zoete V J Med Chem. 2021 Feb 25;64(4):2205-2227. doi: 10.1021/acs.jmedchem.0c01968. Epub , 2021 Feb 8. PMID:33557523[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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