4coh: Difference between revisions
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==Crystal structure of Trypanosoma cruzi CYP51 bound to the sulfonamide derivative of the 4-aminopyridyl-based inhibitor== | ==Crystal structure of Trypanosoma cruzi CYP51 bound to the sulfonamide derivative of the 4-aminopyridyl-based inhibitor== | ||
<StructureSection load='4coh' size='340' side='right' caption='[[4coh]], [[Resolution|resolution]] 2.08Å' scene=''> | <StructureSection load='4coh' size='340' side='right' caption='[[4coh]], [[Resolution|resolution]] 2.08Å' scene=''> | ||
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=T9H:2-FLUORANYL-N-[(2R)-3-(1H-INDOL-3-YL)-1-OXIDANYLIDENE-1-(PYRIDIN-4-YLAMINO)PROPAN-2-YL]-4-(4-THIOPHEN-2-YLSULFONYLPIPERAZIN-1-YL)BENZAMIDE'>T9H</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=T9H:2-FLUORANYL-N-[(2R)-3-(1H-INDOL-3-YL)-1-OXIDANYLIDENE-1-(PYRIDIN-4-YLAMINO)PROPAN-2-YL]-4-(4-THIOPHEN-2-YLSULFONYLPIPERAZIN-1-YL)BENZAMIDE'>T9H</scene></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=4coh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4coh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4coh RCSB], [http://www.ebi.ac.uk/pdbsum/4coh 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=4coh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4coh OCA], [http://pdbe.org/4coh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4coh RCSB], [http://www.ebi.ac.uk/pdbsum/4coh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4coh ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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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 4coh" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 09:07, 5 August 2016
Crystal structure of Trypanosoma cruzi CYP51 bound to the sulfonamide derivative of the 4-aminopyridyl-based inhibitorCrystal structure of Trypanosoma cruzi CYP51 bound to the sulfonamide derivative of the 4-aminopyridyl-based inhibitor
Structural highlights
Function[CP51_TRYCC] Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol (By similarity). Favors C4 dimethylated substrates, the substrate preference order is 24-methylenedihydrolanosterol > 24,25-dihydrolanosterol > lanosterol > obtusifoliol > norlanosterol.[1] [UniProtKB:P0A512] Publication Abstract from PubMedChagas disease is a chronic infection caused by the protozoan parasite Trypanosoma cruzi, manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Therapeutic options to prevent or treat Chagas disease are limited. CYP51, the enzyme key to the biosynthesis of eukaryotic membrane sterols, is a validated drug target in both fungi and T. cruzi. Sulfonamide derivatives of 4-aminopyridyl-based inhibitors of T. cruzi CYP51 (TcCYP51), including the sub-nanomolar compound 3, have molecular structures distinct from other validated CYP51 inhibitors. They augment the biologically relevant chemical space of molecules targeting TcCYP51. In a 2.08 A X-ray structure, TcCYP51 is in a conformation that has been influenced by compound 3 and is distinct from the previously characterized ground-state conformation of CYP51 drug-target complexes. That the binding site was modulated in response to an incoming inhibitor for the first time characterizes TcCYP51 as a flexible target rather than a rigid template. Expanding the Binding Envelope of CYP51 Inhibitors Targeting Trypanosoma cruzi with 4-Aminopyridyl-Based Sulfonamide Derivatives.,Vieira DF, Choi JY, Roush WR, Podust LM Chembiochem. 2014 Apr 25. doi: 10.1002/cbic.201402027. PMID:24771705[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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