title: Structure-function analysis of cytochromes P450 2B.
abstract: In the last 4 years, breakthroughs were made in the field of P450 2B (CYP2B) structure-function through determination of one ligand-free and two inhibitor-bound X-ray crystal structures of CYP2B4, which revealed many of the structural features required for binding ligands of different size and shape. Large conformational changes of several plastic regions of CYP2B4 can dramatically reshape the active site of the enzyme to fit the size and shape of the bound ligand without perturbing the overall P450 fold. Solution biophysical studies using isothermal titration calorimetry (ITC) have revealed the large difference in the thermodynamic parameters of CYP2B4 in binding inhibitors of different ring chemistry and side chains. Other studies have revealed that the effects of site-specific mutations on steady-state kinetic parameters and mechanism-based inactivation are often substrate dependent. These findings agree with the structural data that the enzymes adopt different conformations to bind various ligands. Thus, the substrate specificity of an individual enzyme is determined not only by active site residues but also non-active site residues that modulate conformational changes that are important for substrate access and rearrangement of the active site to accommodate the bound substrate.
authors.affiliation: Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77555-1031, USA. yozhao@utmb.edu
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Zhao
authors.forename: James R
authors.initials: JR
authors.lastname: Halpert
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry* / Q000235:genetics; D001665:Binding Sites; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010089:Oxidoreductases, N-Demethylating / Q000737:chemistry / Q000235:genetics; D011110:Polymorphism, Genetic; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D000072467:Cytochrome P450 Family 2; C465241:cytochrome P-450 CYP2B4 (rabbit); D010089:Oxidoreductases, N-Demethylating