6cr2: Difference between revisions

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New page: '''Unreleased structure''' The entry 6cr2 is ON HOLD Authors: Friggeri, L., Hargrove, T.Y., Wawrzak, Z., Lepesheva, G.I. Description: Crystal structure of sterol 14-alpha demethylase (...
 
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'''Unreleased structure'''


The entry 6cr2 is ON HOLD
==Crystal structure of sterol 14-alpha demethylase (CYP51B) from Aspergillus fumigatus in complex with the VNI derivative N-(1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzamide==
<StructureSection load='6cr2' size='340' side='right'caption='[[6cr2]], [[Resolution|resolution]] 2.38&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6cr2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_fumigatus_Af293 Aspergillus fumigatus Af293]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CR2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CR2 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]] 2.38&#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=LFV:~{N}-[(1~{R})-1-(2,4-dichlorophenyl)-2-imidazol-1-yl-ethyl]-4-[5-[2-fluoranyl-4-[2,2,2-tris(fluoranyl)ethoxy]phenyl]-1,3,4-oxadiazol-2-yl]benzamide'>LFV</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=6cr2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cr2 OCA], [https://pdbe.org/6cr2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cr2 RCSB], [https://www.ebi.ac.uk/pdbsum/6cr2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cr2 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CP51B_ASPFU CP51B_ASPFU] Sterol 14alpha-demethylase, encoded by cyp51A and cyp51B, that plays a critical role in the third module of ergosterol biosynthesis pathway, being ergosterol the major sterol component in fungal membranes that participates in a variety of functions (PubMed:18191972, PubMed:26269599, PubMed:26459890, PubMed:29439966, PubMed:9184358). The third module or late pathway involves the ergosterol synthesis itself through consecutive reactions that mainly occur in the endoplasmic reticulum (ER) membrane (By similarity). In filamentous fungi, during the initial step of this module, lanosterol (lanosta-8,24-dien-3beta-ol) can be metabolized to eburicol (PubMed:18191972, PubMed:26459890, PubMed:29439966). Sterol 14alpha-demethylase catalyzes the three-step oxidative removal of the 14alpha-methyl group (C-32) of both these sterols in the form of formate, and converts eburicol and lanosterol to 14-demethyleburicol (4,4,24-trimethylergosta-8,14,24(28)-trienol) and 4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol, respectively, which are further metabolized by other enzymes in the pathway to ergosterol (PubMed:18191972, PubMed:26269599, PubMed:26459890, PubMed:28461309, PubMed:29439966). Can also use substrates not intrinsic to fungi, such as 24,25-dihydrolanosterol (DHL), producing 4,4'-dimethyl-8,14-cholestadien-3-beta-ol, but at lower rates than the endogenous substrates (By similarity).[UniProtKB:P10614]<ref>PMID:18191972</ref> <ref>PMID:26269599</ref> <ref>PMID:26459890</ref> <ref>PMID:28461309</ref> <ref>PMID:29439966</ref> <ref>PMID:9184358</ref>  As a target of azole drugs, plays a crucial role in azole susceptibility.<ref>PMID:12543662</ref> <ref>PMID:26269599</ref> <ref>PMID:28461309</ref> <ref>PMID:29894182</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Because of the increase in the number of immunocompromised patients, the incidence of invasive fungal infections is growing, but the treatment efficiency remains unacceptably low. The most potent clinical systemic antifungals (azoles) are the derivatives of two scaffolds: ketoconazole and fluconazole. Being the safest antifungal drugs, they still have shortcomings, mainly because of pharmacokinetics and resistance. Here, we report the successful use of the target fungal enzyme, sterol 14alpha-demethylase (CYP51), for structure-based design of novel antifungal drug candidates by minor modifications of VNI [( R)- N-(1-(2,4-dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)], an inhibitor of protozoan CYP51 that cures Chagas disease. The synthesis of fungi-oriented VNI derivatives, analysis of their potencies to inhibit CYP51s from two major fungal pathogens ( Aspergillus fumigatus and Candida albicans), microsomal stability, effects in fungal cells, and structural characterization of A. fumigatus CYP51 in complexes with the most potent compound are described, offering a new antifungal drug scaffold and outlining directions for its further optimization.


Authors: Friggeri, L., Hargrove, T.Y., Wawrzak, Z., Lepesheva, G.I.
Sterol 14alpha-Demethylase Structure-Based Design of VNI (( R)- N-(1-(2,4-Dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)) Derivatives To Target Fungal Infections: Synthesis, Biological Evaluation, and Crystallographic Analysis.,Friggeri L, Hargrove TY, Wawrzak Z, Blobaum AL, Rachakonda G, Lindsley CW, Villalta F, Nes WD, Botta M, Guengerich FP, Lepesheva GI J Med Chem. 2018 Jun 25. doi: 10.1021/acs.jmedchem.8b00641. PMID:29894182<ref>PMID:29894182</ref>


Description: Crystal structure of sterol 14-alpha demethylase (CYP51B) from Aspergillus fumigatus in complex with the VNI derivative N-(1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzamide
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Wawrzak, Z]]
<div class="pdbe-citations 6cr2" style="background-color:#fffaf0;"></div>
[[Category: Hargrove, T.Y]]
== References ==
[[Category: Lepesheva, G.I]]
<references/>
[[Category: Friggeri, L]]
__TOC__
</StructureSection>
[[Category: Aspergillus fumigatus Af293]]
[[Category: Large Structures]]
[[Category: Friggeri L]]
[[Category: Hargrove TY]]
[[Category: Lepesheva GI]]
[[Category: Wawrzak Z]]
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