3gw9

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[[Image:3gw9.png|left|200px]]
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==Crystal structure of sterol 14-alpha demethylase (CYP51) from Trypanosoma brucei bound to an inhibitor N-(1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxaziazol-2-yl)benzamide==
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<StructureSection load='3gw9' size='340' side='right' caption='[[3gw9]], [[Resolution|resolution]] 1.87&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3gw9]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_brucei Trypanosoma brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3GW9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3GW9 FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=VNI:N-[(1R)-1-(2,4-DICHLOROPHENYL)-2-(1H-IMIDAZOL-1-YL)ETHYL]-4-(5-PHENYL-1,3,4-OXADIAZOL-2-YL)BENZAMIDE'>VNI</scene><br>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3g1q|3g1q]]</td></tr>
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<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP51, Tb11.02.4080 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5691 Trypanosoma brucei])</td></tr>
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<tr><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3gw9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gw9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3gw9 RCSB], [http://www.ebi.ac.uk/pdbsum/3gw9 PDBsum]</span></td></tr>
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<table>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gw/3gw9_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Sterol 14alpha-demethylase (14DM, the CYP51 family of cytochrome P450) is an essential enzyme in sterol biosynthesis in eukaryotes. It serves as a major drug target for fungal diseases and can potentially become a target for treatment of human infections with protozoa. Here we present 1.9 A resolution crystal structures of 14DM from the protozoan pathogen Trypanosoma brucei, ligand-free and complexed with a strong chemically selected inhibitor N-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxad i-azol-2-yl)benzamide that we previously found to produce potent antiparasitic effects in Trypanosomatidae. This is the first structure of a eukaryotic microsomal 14DM that acts on sterol biosynthesis, and it differs profoundly from that of the water-soluble CYP51 family member from Mycobacterium tuberculosis, both in organization of the active site cavity and in the substrate access channel location. Inhibitor binding does not cause large scale conformational rearrangements, yet induces unanticipated local alterations in the active site, including formation of a hydrogen bond network that connects, via the inhibitor amide group fragment, two remote functionally essential protein segments and alters the heme environment. The inhibitor binding mode provides a possible explanation for both its functionally irreversible effect on the enzyme activity and its selectivity toward the 14DM from human pathogens versus the human 14DM ortholog. The structures shed new light on 14DM functional conservation and open an excellent opportunity for directed design of novel antiparasitic drugs.
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Crystal structures of Trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections.,Lepesheva GI, Park HW, Hargrove TY, Vanhollebeke B, Wawrzak Z, Harp JM, Sundaramoorthy M, Nes WD, Pays E, Chaudhuri M, Villalta F, Waterman MR J Biol Chem. 2010 Jan 15;285(3):1773-80. Epub 2009 Nov 18. PMID:19923211<ref>PMID:19923211</ref>
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The line below this paragraph, containing "STRUCTURE_3gw9", creates the "Structure Box" on the page.
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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{{STRUCTURE_3gw9| PDB=3gw9 | SCENE= }}
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===Crystal structure of sterol 14-alpha demethylase (CYP51) from Trypanosoma brucei bound to an inhibitor N-(1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxaziazol-2-yl)benzamide===
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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</div>
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== References ==
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<references/>
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The line below this paragraph, {{ABSTRACT_PUBMED_19923211}}, adds the Publication Abstract to the page
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__TOC__
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(as it appears on PubMed at http://www.pubmed.gov), where 19923211 is the PubMed ID number.
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</StructureSection>
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{{ABSTRACT_PUBMED_19923211}}
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==About this Structure==
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[[3gw9]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_brucei Trypanosoma brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3GW9 OCA].
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==Reference==
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<ref group="xtra">PMID:019923211</ref><references group="xtra"/>
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[[Category: Sterol 14-demethylase]]
[[Category: Sterol 14-demethylase]]
[[Category: Trypanosoma brucei]]
[[Category: Trypanosoma brucei]]

Revision as of 09:52, 21 May 2014

Crystal structure of sterol 14-alpha demethylase (CYP51) from Trypanosoma brucei bound to an inhibitor N-(1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxaziazol-2-yl)benzamide

3gw9, resolution 1.87Å

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