7e0s: Difference between revisions
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<StructureSection load='7e0s' size='340' side='right'caption='[[7e0s]], [[Resolution|resolution]] 2.71Å' scene=''> | <StructureSection load='7e0s' size='340' side='right'caption='[[7e0s]], [[Resolution|resolution]] 2.71Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E0S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E0S 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]] 2.712Å</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]] 2.712Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=HU6:(1~{R},2~{S})-2-[[(6-bromanyl-1~{H}-indazol-4-yl)amino]methyl]cyclohexan-1-ol'>HU6</scene></td></tr> | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=HU6:(1~{R},2~{S})-2-[[(6-bromanyl-1~{H}-indazol-4-yl)amino]methyl]cyclohexan-1-ol'>HU6</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=7e0s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e0s OCA], [https://pdbe.org/7e0s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e0s RCSB], [https://www.ebi.ac.uk/pdbsum/7e0s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e0s 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=7e0s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e0s OCA], [https://pdbe.org/7e0s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e0s RCSB], [https://www.ebi.ac.uk/pdbsum/7e0s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e0s ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Li G-B]] | [[Category: Li G-B]] | ||
[[Category: Ning X-L]] | [[Category: Ning X-L]] | ||
Latest revision as of 11:41, 17 October 2024
Crystal Structure of Human Indoleamine 2,3-dioxygenagse 1 (hIDO1) Complexed with (1R,2S)-2-(((6-Bromo-1H-indazol-4-yl)amino)methyl)cyclohexan-1-ol (23)Crystal Structure of Human Indoleamine 2,3-dioxygenagse 1 (hIDO1) Complexed with (1R,2S)-2-(((6-Bromo-1H-indazol-4-yl)amino)methyl)cyclohexan-1-ol (23)
Structural highlights
Publication Abstract from PubMedHuman indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson's disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to 23, which manifested IC50 values of 0.64 and 0.04 muM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice. 23 showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar, 23 likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood. X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson's Disease.,Ning XL, Li YZ, Huo C, Deng J, Gao C, Zhu KR, Wang M, Wu YX, Yu JL, Ren YL, Luo ZY, Li G, Chen Y, Wang SY, Peng C, Yang LL, Wang ZY, Wu Y, Qian S, Li GB J Med Chem. 2021 Jun 24;64(12):8303-8332. doi: 10.1021/acs.jmedchem.1c00303. Epub, 2021 Jun 10. PMID:34110158[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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