View source for 7ryb


==S. CEREVISIAE CYP51 Y140H/I471T - double mutant COMPLEXED WITH Voriconazole==
<StructureSection load='7ryb' size='340' side='right'caption='[[7ryb]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7ryb]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_YJM789 Saccharomyces cerevisiae YJM789]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RYB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RYB 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]] 2.9&#8491;</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=VOR:VORICONAZOLE'>VOR</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=7ryb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ryb OCA], [https://pdbe.org/7ryb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ryb RCSB], [https://www.ebi.ac.uk/pdbsum/7ryb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ryb ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CP51_YEAST CP51_YEAST] Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.
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== Publication Abstract from PubMed ==
Target-based azole resistance in Candida albicans involves overexpression of the ERG11 gene encoding lanosterol 14alpha-demethylase (LDM), and/or the presence of single or multiple mutations in this enzyme. Overexpression of Candida albicans LDM (CaLDM) Y132H I471T by the Darlington strain strongly increased resistance to the short-tailed azoles fluconazole and voriconazole, and weakly increased resistance to the longer-tailed azoles VT-1161, itraconazole and posaconazole. We have used, as surrogates, structurally aligned mutations in recombinant hexahistidine-tagged full-length Saccharomyces cerevisiae LDM6xHis (ScLDM6xHis) to elucidate how differential susceptibility to azole drugs is conferred by LDM of the C. albicans Darlington strain. The mutations Y140H and I471T were introduced, either alone or in combination, into ScLDM6xHis via overexpression of the recombinant enzyme from the PDR5 locus of an azole hypersensitive strain of S. cerevisiae. Phenotypes and high-resolution X-ray crystal structures were determined for the surrogate enzymes in complex with representative short-tailed (voriconazole) and long-tailed (itraconazole) triazoles. The preferential high-level resistance to short-tailed azoles conferred by the ScLDM Y140H I471T mutant required both mutations, despite the I471T mutation conferring only a slight increase in resistance. Crystal structures did not detect changes in the position/tilt of the heme co-factor of wild-type ScLDM, I471T and Y140H single mutants, or the Y140H I471T double-mutant. The mutant threonine sidechain in the Darlington strain CaLDM perturbs the environment of the neighboring C-helix, affects the electronic environment of the heme, and may, via differences in closure of the neck of the substrate entry channel, increase preferential competition between lanosterol and short-tailed azole drugs.

Structural Insights into the Azole Resistance of the Candida albicans Darlington Strain Using Saccharomyces cerevisiae Lanosterol 14alpha-Demethylase as a Surrogate.,Graham DO, Wilson RK, Ruma YN, Keniya MV, Tyndall JDA, Monk BC J Fungi (Basel). 2021 Oct 24;7(11). pii: jof7110897. doi: 10.3390/jof7110897. PMID:34829185<ref>PMID:34829185</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7ryb" style="background-color:#fffaf0;"></div>

==See Also==
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Saccharomyces cerevisiae YJM789]]
[[Category: Graham DO]]
[[Category: Keniya MV]]
[[Category: Monk BC]]
[[Category: Ruma YN]]
[[Category: Tyndall JD]]
[[Category: Wilson RK]]