7zxd
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7zxd]] is a 3 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=7ZXD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZXD FirstGlance]. <br> | <table><tr><td colspan='2'>[[7zxd]] is a 3 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=7ZXD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZXD FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=KB9:1-[1-(2-piperidin-4-ylethyl)-5-pyridin-4-yl-indol-2-yl]butan-1-one'>KB9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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]] 2.09Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=KB9:1-[1-(2-piperidin-4-ylethyl)-5-pyridin-4-yl-indol-2-yl]butan-1-one'>KB9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7zxd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zxd OCA], [https://pdbe.org/7zxd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zxd RCSB], [https://www.ebi.ac.uk/pdbsum/7zxd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zxd 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=7zxd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zxd OCA], [https://pdbe.org/7zxd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zxd RCSB], [https://www.ebi.ac.uk/pdbsum/7zxd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zxd ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == 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> | [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 == | ||
| - | Mycobacterium tuberculosis (Mtb) was responsible for approximately 1.6 million deaths in 2021. With the emergence of extensive drug resistance, novel therapeutic agents are urgently needed, and continued drug discovery efforts required. Host-derived lipids such as cholesterol support Mtb growth, and are also suspected to function in immunomodulation, with links to persistence and immune evasion. Mtb cytochrome P450 (CYP) enzymes facilitate key steps in lipid catabolism and thus present potential targets for inhibition. Here we present a series of compounds based on an ethyl 5-(pyridin-4-yl)-1H-indole-2-carboxylate pharmacophore which bind strongly to both Mtb cholesterol oxidases CYP125 and CYP142. Using a structure-guided approach, combined with biophysical characterization, compounds with micromolar range in-cell activity against clinically relevant drug-resistant isolates were obtained. These will support further development of much-needed additional treatment options and provide routes to probe the role of CYP125 and CYP142 in Mtb pathogenesis. | ||
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| - | Structure Based Discovery of Inhibitors of CYP125 and CYP142 from Mycobacterium tuberculosis.,Katariya MM, Snee M, Tunnicliffe RB, Kavanagh ME, Boshoff HIM, Amadi CN, Levy CW, Munro AW, Abell C, Leys D, Coyne AG, McLean KJ Chemistry. 2023 Mar 13:e202203868. doi: 10.1002/chem.202203868. PMID:36912255<ref>PMID:36912255</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 7zxd" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Crystal structure of CYP125 from Mycobacterium tuberculosis in complex with an inhibitor
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