6e8q: Difference between revisions
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The | ==S. CEREVISIAE CYP51 COMPLEXED WITH Posaconazole== | ||
<StructureSection load='6e8q' size='340' side='right'caption='[[6e8q]], [[Resolution|resolution]] 2.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6e8q]] 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=6E8Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6E8Q 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]] 2.2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=LMT:DODECYL-BETA-D-MALTOSIDE'>LMT</scene>, <scene name='pdbligand=X2N:POSACONAZOLE'>X2N</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=6e8q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e8q OCA], [https://pdbe.org/6e8q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6e8q RCSB], [https://www.ebi.ac.uk/pdbsum/6e8q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6e8q ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/A6ZSR0_YEAS7 A6ZSR0_YEAS7] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Tetrazole antifungals designed to target fungal lanosterol 14alpha-demethylase (LDM) appear to be effective against a range of fungal pathogens. In addition, a crystal structure of the catalytic domain of Candida albicans LDM in complex with the tetrazole VT-1161 has been obtained. We have addressed concern about artifacts that might arise from crystallizing VT-1161 with truncated recombinant CYP51s and measured the impact on VT-1161 susceptibility of genotypes known to confer azole resistance. A yeast system was used to overexpress recombinant full-length Saccharomyces cerevisiae LDM with a C-terminal hexahistidine tag (ScLDM6xHis) for phenotypic analysis and crystallographic studies with VT-1161 or with the widely used triazole drug posaconazole (PCZ). We determined the effect of characterized mutations in LDM on VT-1161 activity and identified drug efflux pumps from fungi, including key fungal pathogens, that efflux VT-1161. The relevance of these yeast-based observations on drug efflux was verified using clinical isolates of C. albicans and Candida glabrata VT-1161 binding elicits a significant conformational difference between the full-length and truncated enzymes not found when posaconazole is bound. Susceptibility to VT-1161 is reduced by ATP-binding cassette (ABC) and major facilitator superfamily (MFS) drug efflux pumps, the overexpression of LDM, and mutations within the drug binding pocket of LDM that affect interaction with the tertiary alcohol of the drug. | |||
Azole Resistance Reduces Susceptibility to the Tetrazole Antifungal VT-1161.,Monk BC, Keniya MV, Sabherwal M, Wilson RK, Graham DO, Hassan HF, Chen D, Tyndall JDA Antimicrob Agents Chemother. 2018 Dec 21;63(1). pii: AAC.02114-18. doi:, 10.1128/AAC.02114-18. Print 2019 Jan. PMID:30397057<ref>PMID:30397057</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6e8q" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: Sabherwal | ==See Also== | ||
[[Category: | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Saccharomyces cerevisiae YJM789]] | |||
[[Category: Keniya MV]] | |||
[[Category: Monk BC]] | |||
[[Category: Sabherwal M]] | |||
[[Category: Tyndall JD]] | |||
Latest revision as of 09:21, 11 October 2023
S. CEREVISIAE CYP51 COMPLEXED WITH PosaconazoleS. CEREVISIAE CYP51 COMPLEXED WITH Posaconazole
Structural highlights
FunctionPublication Abstract from PubMedTetrazole antifungals designed to target fungal lanosterol 14alpha-demethylase (LDM) appear to be effective against a range of fungal pathogens. In addition, a crystal structure of the catalytic domain of Candida albicans LDM in complex with the tetrazole VT-1161 has been obtained. We have addressed concern about artifacts that might arise from crystallizing VT-1161 with truncated recombinant CYP51s and measured the impact on VT-1161 susceptibility of genotypes known to confer azole resistance. A yeast system was used to overexpress recombinant full-length Saccharomyces cerevisiae LDM with a C-terminal hexahistidine tag (ScLDM6xHis) for phenotypic analysis and crystallographic studies with VT-1161 or with the widely used triazole drug posaconazole (PCZ). We determined the effect of characterized mutations in LDM on VT-1161 activity and identified drug efflux pumps from fungi, including key fungal pathogens, that efflux VT-1161. The relevance of these yeast-based observations on drug efflux was verified using clinical isolates of C. albicans and Candida glabrata VT-1161 binding elicits a significant conformational difference between the full-length and truncated enzymes not found when posaconazole is bound. Susceptibility to VT-1161 is reduced by ATP-binding cassette (ABC) and major facilitator superfamily (MFS) drug efflux pumps, the overexpression of LDM, and mutations within the drug binding pocket of LDM that affect interaction with the tertiary alcohol of the drug. Azole Resistance Reduces Susceptibility to the Tetrazole Antifungal VT-1161.,Monk BC, Keniya MV, Sabherwal M, Wilson RK, Graham DO, Hassan HF, Chen D, Tyndall JDA Antimicrob Agents Chemother. 2018 Dec 21;63(1). pii: AAC.02114-18. doi:, 10.1128/AAC.02114-18. Print 2019 Jan. PMID:30397057[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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