2w0a: Difference between revisions

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-[[Image:2w0a.png|left|200px]]
-<!--
+==CYP51 of M. tuberculosis bound to an inhibitor N-[(1S)-2-METHYL-1-(PYRIDIN-4-YLCARBAMOYL)PROPYL]CYCLOHEXANECARBOXAMIDE==
-The line below this paragraph, containing "STRUCTURE_2w0a", creates the "Structure Box" on the page.
+<StructureSection load='2w0a' size='340' side='right'caption='[[2w0a]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[2w0a]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W0A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2W0A FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CII:N-[(1S)-2-METHYL-1-(PYRIDIN-4-YLCARBAMOYL)PROPYL]CYCLOHEXANECARBOXAMIDE'>CII</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
-{{STRUCTURE_2w0a|  PDB=2w0a  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2w0a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w0a OCA], [https://pdbe.org/2w0a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2w0a RCSB], [https://www.ebi.ac.uk/pdbsum/2w0a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2w0a ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/CP51_MYCTU CP51_MYCTU] Its precise biological substrate is not known. Catalyzes C14-demethylation of lanosterol, 24,25-dihydrolanosterol and obtusifoliol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.<ref>PMID:9756611</ref> <ref>PMID:10430874</ref>
+== 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/w0/2w0a_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=2w0a ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+BACKGROUND: The two front-line drugs for chronic Trypanosoma cruzi infections are limited by adverse side-effects and declining efficacy. One potential new target for Chagas' disease chemotherapy is sterol 14alpha-demethylase (CYP51), a cytochrome P450 enzyme involved in biosynthesis of membrane sterols. METHODOLOGY/PRINCIPAL FINDING: In a screening effort targeting Mycobacterium tuberculosis CYP51 (CYP51(Mt)), we previously identified the N-[4-pyridyl]-formamide moiety as a building block capable of delivering a variety of chemotypes into the CYP51 active site. In that work, the binding modes of several second generation compounds carrying this scaffold were determined by high-resolution co-crystal structures with CYP51(Mt). Subsequent assays against the CYP51 orthologue in T. cruzi, CYP51(Tc), demonstrated that two of the compounds tested in the earlier effort bound tightly to this enzyme. Both were tested in vitro for inhibitory effects against T. cruzi and the related protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. One of the compounds had potent, selective anti-T. cruzi activity in infected mouse macrophages. Cure of treated host cells was confirmed by prolonged incubation in the absence of the inhibiting compound. Discrimination between T. cruzi and T. brucei CYP51 by the inhibitor was largely based on the variability (phenylalanine versus isoleucine) of a single residue at a critical position in the active site. CONCLUSIONS/SIGNIFICANCE: CYP51(Mt)-based crystal structure analysis revealed that the functional groups of the two tightly bound compounds are likely to occupy different spaces in the CYP51 active site, suggesting the possibility of combining the beneficial features of both inhibitors in a third generation of compounds to achieve more potent and selective inhibition of CYP51(Tc).
-===CYP51 OF M. TUBERCULOSIS BOUND TO AN INHIBITOR N-[(1S)-2-METHYL-1-(PYRIDIN-4-YLCARBAMOYL)PROPYL] CYCLOHEXANECARBOXAMIDE===
+Trypanosoma cruzi CYP51 Inhibitor Derived from a Mycobacterium tuberculosis Screen Hit.,Chen CK, Doyle PS, Yermalitskaya LV, Mackey ZB, Ang KK, McKerrow JH, Podust LM PLoS Negl Trop Dis. 2009;3(2):e372. Epub 2009 Feb 3. PMID:19190730<ref>PMID:19190730</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-<!--
+</div>
-The line below this paragraph, {{ABSTRACT_PUBMED_19190730}}, adds the Publication Abstract to the page
+<div class="pdbe-citations 2w0a" style="background-color:#fffaf0;"></div>
-(as it appears on PubMed at http://www.pubmed.gov), where 19190730 is the PubMed ID number.
--->
-{{ABSTRACT_PUBMED_19190730}}
-==About this Structure==
-[[2w0a]] is a 1 chain structure of [[Cytochrome P450]] with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W0A OCA].
 ==See Also==
-*[[Cytochrome P450]]
+*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:19190730</ref><references group="xtra"/>
+__TOC__
-[[Category: Mycobacterium tuberculosis]]
+</StructureSection>
-[[Category: Sterol 14-demethylase]]
+[[Category: Large Structures]]
-[[Category: Podust, L M.]]
+[[Category: Mycobacterium tuberculosis H37Rv]]
-[[Category: Cytoplasm]]
+[[Category: Podust LM]]
-[[Category: Heme]]
-[[Category: Iron]]
-[[Category: Lipid synthesis]]
-[[Category: Metal-binding]]
-[[Category: Monooxygenase]]
-[[Category: Nadp]]
-[[Category: Oxidoreductase]]
-[[Category: Protein-inhibitor complex]]
-[[Category: Steroid biosynthesis]]
-[[Category: Sterol biosynthesis]]
-[[Category: X-ray diffraction]]