5eah: Difference between revisions

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 ==Saccharomyces cerevisiae CYP51 complexed with the plant pathogen inhibitor Difenoconazole==
-<StructureSection load='5eah' size='340' side='right' caption='[[5eah]], [[Resolution|resolution]] 2.54&Aring;' scene=''>
+<StructureSection load='5eah' size='340' side='right'caption='[[5eah]], [[Resolution|resolution]] 2.54&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5eah]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EAH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EAH FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5eah]] 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=5EAH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EAH FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5LW:1-[[(2~{S},4~{S})-2-[2-CHLORANYL-4-(4-CHLORANYLPHENOXY)PHENYL]-4-METHYL-1,3-DIOXOLAN-2-YL]METHYL]-1,2,4-TRIAZOLE'>5LW</scene>, <scene name='pdbligand=5LX:1-[[(2~{R},4~{S})-2-[2-CHLORANYL-4-(4-CHLORANYLPHENOXY)PHENYL]-4-METHYL-1,3-DIOXOLAN-2-YL]METHYL]-1,2,4-TRIAZOLE'>5LX</scene>, <scene name='pdbligand=5LY:1-[[(2~{R},4~{R})-2-[2-CHLORANYL-4-(4-CHLORANYLPHENOXY)PHENYL]-4-METHYL-1,3-DIOXOLAN-2-YL]METHYL]-1,2,4-TRIAZOLE'>5LY</scene>, <scene name='pdbligand=5LZ:1-[[(2~{S},4~{R})-2-[2-CHLORANYL-4-(4-CHLORANYLPHENOXY)PHENYL]-4-METHYL-1,3-DIOXOLAN-2-YL]METHYL]-1,2,4-TRIAZOLE'>5LZ</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</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]] 2.541&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4wmz|4wmz]], [[5eab|5eab]], [[5eac|5eac]], [[5ead|5ead]], [[5eae|5eae]], [[5eaf|5eaf]], [[5eag|5eag]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5LW:1-[[(2~{S},4~{S})-2-[2-CHLORANYL-4-(4-CHLORANYLPHENOXY)PHENYL]-4-METHYL-1,3-DIOXOLAN-2-YL]METHYL]-1,2,4-TRIAZOLE'>5LW</scene>, <scene name='pdbligand=5LX:1-[[(2~{R},4~{S})-2-[2-CHLORANYL-4-(4-CHLORANYLPHENOXY)PHENYL]-4-METHYL-1,3-DIOXOLAN-2-YL]METHYL]-1,2,4-TRIAZOLE'>5LX</scene>, <scene name='pdbligand=5LY:1-[[(2~{R},4~{R})-2-[2-CHLORANYL-4-(4-CHLORANYLPHENOXY)PHENYL]-4-METHYL-1,3-DIOXOLAN-2-YL]METHYL]-1,2,4-TRIAZOLE'>5LY</scene>, <scene name='pdbligand=5LZ:1-[[(2~{S},4~{R})-2-[2-CHLORANYL-4-(4-CHLORANYLPHENOXY)PHENYL]-4-METHYL-1,3-DIOXOLAN-2-YL]METHYL]-1,2,4-TRIAZOLE'>5LZ</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
-<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=5eah FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eah OCA], [http://pdbe.org/5eah PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5eah RCSB], [http://www.ebi.ac.uk/pdbsum/5eah PDBsum]</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=5eah FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eah OCA], [https://pdbe.org/5eah PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5eah RCSB], [https://www.ebi.ac.uk/pdbsum/5eah PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5eah ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/A6ZSR0_YEAS7 A6ZSR0_YEAS7]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-Infections by fungal pathogens such as Candida albicans and Aspergillus fumigatus and their resistance to triazole drugs are major concerns. Fungal lanosterol 14alpha-demethylase belongs to the CYP51 class in the cytochrome P450 superfamily of enzymes. This monospanning bitopic membrane protein is involved in ergosterol biosynthesis and is the primary target of azole antifungal drugs, including fluconazole. The lack of high resolution structural information for this drug target from fungal pathogens has been a limiting factor for the design of modified triazole drugs that will overcome resistance. Here we report the X-ray structure of full-length Saccharomyces cerevisiae lanosterol 14alpha-demethylase in complex with fluconazole at a resolution of 2.05 A. This structure shows the key interactions involved in fluconazole binding and provides insight into resistance mechanisms by revealing a water mediated hydrogen bonding network between the drug and Tyrosine140, a residue frequently found mutated to histidine or phenylalanine in resistant clinical isolates.
+Azole antifungals, known as demethylase inhibitors (DMIs), target sterol 14alpha-demethylase (CYP51) in the ergosterol biosynthetic pathway of fungal pathogens of both plants and humans. DMIs remain the treatment of choice in crop protection against a wide range of fungal phytopathogens that have the potential to reduce crop yields and threaten food security. We used a yeast membrane protein expression system to overexpress recombinant hexahistidine-tagged S. cerevisiae lanosterol 14alpha-demethylase and the Y140F or Y140H mutants of this enzyme as surrogates in order characterize interactions with DMIs. The whole-cell antifungal activity (MIC50 values) of both the R- and S-enantiomers of tebuconazole, prothioconazole (PTZ), prothioconazole-desthio, and oxo-prothioconazole (oxo-PTZ) as well as for fluquinconazole, prochloraz and a racemic mixture of difenoconazole were determined. In vitro binding studies with the affinity purified enzyme were used to show tight type II binding to the yeast enzyme for all compounds tested except PTZ and oxo-PTZ. High resolution X-ray crystal structures of ScErg11p6xHis in complex with seven DMIs, including four enantiomers, reveal triazole-mediated coordination of all compounds and the specific orientation of compounds within the relatively hydrophobic binding site. Comparison with CYP51 structures from fungal pathogens including Candida albicans, Candida glabrata and Aspergillus fumigatus provides strong evidence for a highly conserved CYP51 structure including the drug binding site. The structures obtained using S. cerevisiae lanosterol 14alpha-demethylase in complex with these agrochemicals provide the basis for understanding the impact of mutations on azole susceptibility and a platform for the structure-directed design of the next-generation of DMIs.
-Structural insights into binding of the antifungal drug fluconazole to Saccharomyces cerevisiae lanosterol 14alpha-demethylase.,Sagatova A, Keniya MV, Wilson RK, Monk BC, Tyndall JD Antimicrob Agents Chemother. 2015 Jun 8. pii: AAC.00925-15. PMID:26055382<ref>PMID:26055382</ref>
+Structural and Functional Elucidation of Yeast Lanosterol 14alpha-Demethylase in Complex with Agrochemical Antifungals.,Tyndall JD, Sabherwal M, Sagatova AA, Keniya MV, Negroni J, Wilson RK, Woods MA, Tietjen K, Monk BC PLoS One. 2016 Dec 1;11(12):e0167485. doi: 10.1371/journal.pone.0167485., eCollection 2016. PMID:27907120<ref>PMID:27907120</ref>
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
 <div class="pdbe-citations 5eah" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Keniya, M V]]
+[[Category: Large Structures]]
-[[Category: Monk, B C]]
+[[Category: Saccharomyces cerevisiae YJM789]]
-[[Category: Sabherwal, M]]
+[[Category: Keniya MV]]
-[[Category: Tyndall, J D.A]]
+[[Category: Monk BC]]
-[[Category: Wilson, R K]]
+[[Category: Sabherwal M]]
-[[Category: Woods, M V]]
+[[Category: Tyndall JDA]]
-[[Category: Cyp51]]
+[[Category: Wilson RK]]
-[[Category: Difenoconazole]]
+[[Category: Woods MV]]
-[[Category: Oxidoreductase-oxidoreducatse inhibitor complex]]
-[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
-[[Category: Racemic mixture]]