2xc3: Difference between revisions
New page: '''Unreleased structure''' The entry 2xc3 is ON HOLD until sometime in the future Authors: Ouellet, H., Ortiz de Montellano, P.R., Podust, L.M. Description: X-ray structure of CYP125A1... |
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==X-ray structure of Mycobacterium tuberculosis cyp125 bound to the reverse type I inhibitor== | |||
<StructureSection load='2xc3' size='340' side='right'caption='[[2xc3]], [[Resolution|resolution]] 1.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2xc3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XC3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XC3 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]] 1.5Å</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=RT8:NALPHA-[(TRANS-4-METHYLCYCLOHEXYL)CARBONYL]-N-PYRIDIN-4-YL-D-TRYPTOPHANAMIDE'>RT8</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=2xc3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xc3 OCA], [https://pdbe.org/2xc3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xc3 RCSB], [https://www.ebi.ac.uk/pdbsum/2xc3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xc3 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CP125_MYCTU CP125_MYCTU] Catalyzes the C-27 hydroxylation of cholest-4-en-3-one and cholesterol and subsequently oxidizes the alcohol of the former to the cholest-4-en-3-one-27-oic acid via the aldehyde intermediate. Not required to incorporate the cholesterol side-chain carbon atoms into cellular lipids.<ref>PMID:19846551</ref> <ref>PMID:20545858</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Cytochrome P450 CYP125A1 of Mycobacteriumtuberculosis, a potential therapeutic target for tuberculosis in humans, initiates degradation of the aliphatic chain of host cholesterol and is essential for establishing M. tuberculosis infection in a mouse model of disease. We explored the interactions of CYP125A1 with a reverse type I inhibitor by X-ray structure analysis and UV-vis spectroscopy. Compound LP10 (alpha-[(4-methylcyclohexyl)carbonyl amino]-N-4-pyridinyl-1H-indole-3-propanamide), previously identified as a potent type II inhibitor of Trypanosomacruzi CYP51, shifts CYP125A1 to a water-coordinated low-spin state upon binding with low micromolar affinity. When LP10 is present in the active site, the crystal structure and spectral characteristics both demonstrate changes in lipophilic and electronic properties favoring coordination of the iron axial water ligand. These results provide an insight into the structural requirements for developing selective CYP125A1 inhibitors. | |||
Reverse type I inhibitor of Mycobacteriumtuberculosis CYP125A1.,Ouellet H, Kells PM, Ortiz de Montellano PR, Podust LM Bioorg Med Chem Lett. 2011 Jan 1;21(1):332-7. Epub 2010 Nov 5. PMID:21109436<ref>PMID:21109436</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2xc3" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis H37Rv]] | |||
[[Category: Kells PM]] | |||
[[Category: Ortiz de Montellano PR]] | |||
[[Category: Ouellet H]] | |||
[[Category: Podust LM]] | |||
Latest revision as of 13:37, 16 August 2023
X-ray structure of Mycobacterium tuberculosis cyp125 bound to the reverse type I inhibitorX-ray structure of Mycobacterium tuberculosis cyp125 bound to the reverse type I inhibitor
Structural highlights
FunctionCP125_MYCTU Catalyzes the C-27 hydroxylation of cholest-4-en-3-one and cholesterol and subsequently oxidizes the alcohol of the former to the cholest-4-en-3-one-27-oic acid via the aldehyde intermediate. Not required to incorporate the cholesterol side-chain carbon atoms into cellular lipids.[1] [2] Publication Abstract from PubMedCytochrome P450 CYP125A1 of Mycobacteriumtuberculosis, a potential therapeutic target for tuberculosis in humans, initiates degradation of the aliphatic chain of host cholesterol and is essential for establishing M. tuberculosis infection in a mouse model of disease. We explored the interactions of CYP125A1 with a reverse type I inhibitor by X-ray structure analysis and UV-vis spectroscopy. Compound LP10 (alpha-[(4-methylcyclohexyl)carbonyl amino]-N-4-pyridinyl-1H-indole-3-propanamide), previously identified as a potent type II inhibitor of Trypanosomacruzi CYP51, shifts CYP125A1 to a water-coordinated low-spin state upon binding with low micromolar affinity. When LP10 is present in the active site, the crystal structure and spectral characteristics both demonstrate changes in lipophilic and electronic properties favoring coordination of the iron axial water ligand. These results provide an insight into the structural requirements for developing selective CYP125A1 inhibitors. Reverse type I inhibitor of Mycobacteriumtuberculosis CYP125A1.,Ouellet H, Kells PM, Ortiz de Montellano PR, Podust LM Bioorg Med Chem Lett. 2011 Jan 1;21(1):332-7. Epub 2010 Nov 5. PMID:21109436[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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