View source for 3gw9


==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==
<StructureSection load='3gw9' size='340' side='right'caption='[[3gw9]], [[Resolution|resolution]] 1.87&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3gw9]] is a 4 chain structure with sequence from [https://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 [https://proteopedia.org/fgij/fg.htm?mol=3GW9 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]] 1.87&#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=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></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=3gw9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gw9 OCA], [https://pdbe.org/3gw9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3gw9 RCSB], [https://www.ebi.ac.uk/pdbsum/3gw9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3gw9 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q385E8_TRYB2 Q385E8_TRYB2] 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gw/3gw9_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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/main_output.php?pdb_ID=3gw9 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

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>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3gw9" style="background-color:#fffaf0;"></div>

==See Also==
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Trypanosoma brucei]]
[[Category: Hargrove TY]]
[[Category: Harp J]]
[[Category: Lepesheva GI]]
[[Category: Waterman MR]]
[[Category: Wawrzak Z]]