5jlc

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<StructureSection load='5jlc' size='340' side='right'caption='[[5jlc]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
<StructureSection load='5jlc' size='340' side='right'caption='[[5jlc]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5jlc]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Canga Canga]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JLC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5JLC FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5jlc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Candida_glabrata_CBS_138 Candida glabrata CBS 138]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JLC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JLC 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=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=1YN:2-[(2R)-BUTAN-2-YL]-4-{4-[4-(4-{[(2R,4S)-2-(2,4-DICHLOROPHENYL)-2-(1H-1,2,4-TRIAZOL-1-YLMETHYL)-1,3-DIOXOLAN-4-YL]METHOXY}PHENYL)PIPERAZIN-1-YL]PHENYL}-2,4-DIHYDRO-3H-1,2,4-TRIAZOL-3-ONE'>1YN</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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]] 2.4&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ERG11, CYP51, CAGL0E04334g ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=284593 CANGA])</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=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=1YN:2-[(2R)-BUTAN-2-YL]-4-{4-[4-(4-{[(2R,4S)-2-(2,4-DICHLOROPHENYL)-2-(1H-1,2,4-TRIAZOL-1-YLMETHYL)-1,3-DIOXOLAN-4-YL]METHOXY}PHENYL)PIPERAZIN-1-YL]PHENYL}-2,4-DIHYDRO-3H-1,2,4-TRIAZOL-3-ONE'>1YN</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></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/Sterol_14-demethylase Sterol 14-demethylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.70 1.14.13.70] </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=5jlc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jlc OCA], [https://pdbe.org/5jlc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jlc RCSB], [https://www.ebi.ac.uk/pdbsum/5jlc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jlc ProSAT]</span></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=5jlc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jlc OCA], [http://pdbe.org/5jlc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5jlc RCSB], [http://www.ebi.ac.uk/pdbsum/5jlc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5jlc ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/CP51_CANGA CP51_CANGA]] 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 (By similarity).
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[https://www.uniprot.org/uniprot/CP51_CANGA CP51_CANGA] 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 (By similarity).
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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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.
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Targeting lanosterol 14alpha-demethylase (LDM) with azole drugs provides prophylaxis and treatments for superficial and disseminated fungal infections, but cure rates are not optimal for immunocompromised patients and individuals with comorbidities. The efficacy of azole drugs has also been reduced due to the emergence of drug-resistant fungal pathogens. We have addressed the need to improve the potency, spectrum, and specificity for azoles by expressing in Saccharomyces cerevisiae functional, recombinant, hexahistidine-tagged, full-length Candida albicans LDM (CaLDM6xHis) and Candida glabrata LDM (CgLDM6xHis) and determining their X-ray crystal structures. The crystal structures of CaLDM6xHis, CgLDM6xHis, and ScLDM6xHis have the same fold and bind itraconazole in nearly identical conformations. The catalytic domains of the full-length LDMs have the same fold as the CaLDM6xHis catalytic domain in complex with posaconazole, with minor structural differences within the ligand binding pocket. Our structures give insight into the LDM reaction mechanism and phenotypes of single-site CaLDM mutations. This study provides a practical basis for the structure-directed discovery of novel antifungals that target LDMs of fungal pathogens.
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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>
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Crystal Structures of Full-Length Lanosterol 14alpha-Demethylases of Prominent Fungal Pathogens Candida albicans and Candida glabrata Provide Tools for Antifungal Discovery.,Keniya MV, Sabherwal M, Wilson RK, Woods MA, Sagatova AA, Tyndall JDA, Monk BC Antimicrob Agents Chemother. 2018 Oct 24;62(11). pii: AAC.01134-18. doi:, 10.1128/AAC.01134-18. Print 2018 Nov. PMID:30126961<ref>PMID:30126961</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
<div class="pdbe-citations 5jlc" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 5jlc" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Canga]]
 
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Sterol 14-demethylase]]
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[[Category: Keniya MV]]
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[[Category: Keniya, M V]]
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[[Category: Monk BC]]
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[[Category: Monk, B C]]
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[[Category: Sabherwal M]]
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[[Category: Sabherwal, M]]
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[[Category: Sagatova AA]]
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[[Category: Sagatova, A A]]
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[[Category: Tyndall JDA]]
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[[Category: Tyndall, J D.A]]
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[[Category: Wilson RK]]
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[[Category: Wilson, R K]]
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[[Category: Candida glabrata]]
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[[Category: Cyp51]]
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[[Category: Itraconazole]]
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[[Category: Oxidoreductase-oxidoreducatse inhibitor complex]]
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[[Category: Pathogen]]
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Current revision

Structure of CYP51 from the pathogen Candida glabrata

PDB ID 5jlc

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