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5opa

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==The crystal structure of P450 CYP121 in complex with lead compound 7b==
==The crystal structure of P450 CYP121 in complex with lead compound 7b==
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<StructureSection load='5opa' size='340' side='right' caption='[[5opa]], [[Resolution|resolution]] 1.34&Aring;' scene=''>
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<StructureSection load='5opa' size='340' side='right'caption='[[5opa]], [[Resolution|resolution]] 1.34&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5opa]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OPA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OPA FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5opa]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_CDC1551 Mycobacterium tuberculosis CDC1551]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OPA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OPA FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A2W:3-(4-fluorophenyl)-4-(imidazol-1-ylmethyl)-1-phenyl-pyrazole'>A2W</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.345&#8491;</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mycocyclosin_synthase Mycocyclosin synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.21.9 1.14.21.9] </span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A2W:3-(4-fluorophenyl)-4-(imidazol-1-ylmethyl)-1-phenyl-pyrazole'>A2W</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5opa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5opa OCA], [http://pdbe.org/5opa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5opa RCSB], [http://www.ebi.ac.uk/pdbsum/5opa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5opa ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5opa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5opa OCA], [https://pdbe.org/5opa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5opa RCSB], [https://www.ebi.ac.uk/pdbsum/5opa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5opa ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/CP121_MYCTO CP121_MYCTO]] Catalyzes C-C bond formation between the carbons ortho to the phenolic hydroxyl of cyclo(L-tyr-L-tyr) (cYY) producing mycocyclosin. Can also use cyclo(L-Tyr-L-Phe) (cYF), cyclo(L-Tyr-L-Trp) (cYW) and cyclo(L-Tyr-L-3,4-dihydroxyphenylalanine) (cY-DOPA) as substrate (By similarity).
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[https://www.uniprot.org/uniprot/CP121_MYCTU CP121_MYCTU]
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Three series of biarylpyrazole imidazole and triazoles are described, which vary in the linker between the biaryl pyrazole and imidazole/triazole group. The imidazole and triazole series with the short -CH2- linker displayed promising antimycobacterial activity, with the imidazole-CH2- series (7) showing low MIC values (6.25-25 mug/mL), which was also influenced by lipophilicity. Extending the linker to -C(O)NH(CH2)2- resulted in a loss of antimycobacterial activity. The binding affinity of the compounds with CYP121A1 was determined by UV-visible optical titrations with KD values of 2.63, 35.6, and 290 muM, respectively, for the tightest binding compounds 7e, 8b, and 13d from their respective series. Both binding affinity assays and docking studies of the CYP121A1 inhibitors suggest type II indirect binding through interstitial water molecules, with key binding residues Thr77, Val78, Val82, Val83, Met86, Ser237, Gln385, and Arg386, comparable with the binding interactions observed with fluconazole and the natural substrate dicyclotyrosine.
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Novel Aryl Substituted Pyrazoles as Small Molecule Inhibitors of Cytochrome P450 CYP121A1: Synthesis and Antimycobacterial Evaluation.,Taban IM, Elshihawy HEAE, Torun B, Zucchini B, Williamson CJ, Altuwairigi D, Ngu AST, McLean KJ, Levy CW, Sood S, Marino LB, Munro AW, de Carvalho LPS, Simons C J Med Chem. 2017 Dec 28;60(24):10257-10267. doi: 10.1021/acs.jmedchem.7b01562., Epub 2017 Dec 7. PMID:29185746<ref>PMID:29185746</ref>
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==See Also==
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*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5opa" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Mycocyclosin synthase]]
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[[Category: Large Structures]]
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[[Category: Levy, C W]]
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[[Category: Mycobacterium tuberculosis CDC1551]]
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[[Category: Cytochrome p450 inhibitor complex]]
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[[Category: Levy CW]]
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[[Category: Oxidoreductase]]
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Current revision

The crystal structure of P450 CYP121 in complex with lead compound 7b

PDB ID 5opa

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