2w0a: Difference between revisions
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<StructureSection load='2w0a' size='340' side='right' caption='[[2w0a]], [[Resolution|resolution]] 1.60Å' scene=''> | <StructureSection load='2w0a' size='340' side='right' caption='[[2w0a]], [[Resolution|resolution]] 1.60Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2w0a]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[2w0a]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2W0A FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2bz9|2bz9]], [[1u13|1u13]], [[2ci0|2ci0]], [[2cib|2cib]], [[1e9x|1e9x]], [[1x8v|1x8v]], [[2vku|2vku]], [[1h5z|1h5z]], [[1ea1|1ea1]], [[2w09|2w09]], [[2w0b|2w0b]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2bz9|2bz9]], [[1u13|1u13]], [[2ci0|2ci0]], [[2cib|2cib]], [[1e9x|1e9x]], [[1x8v|1x8v]], [[2vku|2vku]], [[1h5z|1h5z]], [[1ea1|1ea1]], [[2w09|2w09]], [[2w0b|2w0b]]</td></tr> | ||
<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> | <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> | ||
<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=2w0a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w0a OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2w0a RCSB], [http://www.ebi.ac.uk/pdbsum/2w0a PDBsum]</span></td></tr> | <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=2w0a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w0a OCA], [http://pdbe.org/2w0a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2w0a RCSB], [http://www.ebi.ac.uk/pdbsum/2w0a PDBsum]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
</jmolCheckbox> | </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/ | </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="clear:both"></div> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 2w0a" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Myctu]] | ||
[[Category: Sterol 14-demethylase]] | [[Category: Sterol 14-demethylase]] | ||
[[Category: Podust, L M]] | [[Category: Podust, L M]] | ||
Revision as of 12:48, 8 February 2016
CYP51 OF M. TUBERCULOSIS BOUND TO AN INHIBITOR N-[(1S)-2-METHYL-1-(PYRIDIN-4-YLCARBAMOYL)PROPYL] CYCLOHEXANECARBOXAMIDECYP51 OF M. TUBERCULOSIS BOUND TO AN INHIBITOR N-[(1S)-2-METHYL-1-(PYRIDIN-4-YLCARBAMOYL)PROPYL] CYCLOHEXANECARBOXAMIDE
Structural highlights
Function[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.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBACKGROUND: 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). 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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