6fmo | pdb_00006fmo

Crystal structure of the substrate (obtusifoliol)-bound and ligand-free I105F mutant of sterol 14-alpha demethylase (CYP51) from Trypanosoma cruzi

spinqualitylabelsall models 6fmo, resolution 3.18Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6fmo is a 4 chain structure with sequence from Trycr. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: DVE, HEM Gene: CYP51A (TRYCR) Activity: Sterol 14-demethylase, with EC number 1.14.13.70 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Sterol 14alpha-demethylases (CYP51s) are phylogenetically the most conserved cytochromes P450, whose three-step reaction is crucial for biosynthesis of sterols and serves as a leading target for clinical and agricultural antifungal agents. The structures of several (bacterial, protozoan, fungal, and human) CYP51 orthologs, in both the ligand-free and inhibitor-bound forms, have been determined and have revealed striking similarity at the secondary and tertiary structural levels, despite having low sequence identity. Moreover, in contrast to many of the substrate-promiscuous, drug-metabolizing P450s, CYP51 structures do not display substantial rearrangements in their backbones upon binding of various inhibitory ligands, essentially representing a snapshot of the ligand-free sterol 14alpha-demethylase. Here, using the obtusifoliol-bound I105F variant of Trypanosoma cruzi CYP51, we report that formation of the catalytically competent complex with the physiological substrate triggers a large-scale conformational switch, dramatically reshaping the enzyme active site (3.5-6.0 A movements in the FG-arm, HI-arm, and helix C) in the direction of catalysis. Notably, our X-ray structural analyses revealed that the substrate channel closes, the proton delivery route opens, and the topology and electrostatic potential of the proximal surface reorganize to favor interaction with the electron-donating flavoprotein partner, NADPH-cytochrome P450 reductase. Site-directed mutagenesis of the amino acid residues involved in these events revealed a key role of active-site salt bridges in contributing to the structural dynamics that accompanies CYP51 function. Comparative analysis of apo-CYP51 and its sterol-bound complex provided key conceptual insights into the molecular mechanisms of CYP51 catalysis, functional conservation, lineage-specific substrate complementarity, and druggability differences. Binding of a physiological substrate causes large-scale conformational reorganization in cytochrome P450 51.,Hargrove TY, Wawrzak Z, Fisher PM, Child SA, Nes WD, Guengerich FP, Waterman MR, Lepesheva GI J Biol Chem. 2018 Oct 16. pii: RA118.005850. doi: 10.1074/jbc.RA118.005850. PMID:30327430 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA