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=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4coh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Trycr Trycr]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4COH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4COH FirstGlance]. <br> | <table><tr><td colspan='2'>[[4coh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Trycr Trycr]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4COH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4COH FirstGlance]. <br> | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Sterol 14-demethylase]] | [[Category: Sterol 14-demethylase]] | ||
[[Category: Trycr]] | [[Category: Trycr]] | ||
Revision as of 12:36, 20 March 2019
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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