Structure Of Cytochrome P450 2B4 Research Articles

Structure of cytochrome P450 2B4 with an acetate ligand and an active site hydrogen bond network similar to oxyferrous P450cam

Superposition of the active site of acetate-bound P4502B4 and oxyferrous P450cam. Bond lengths between the heme iron, the sixth ligand, and the hydroxyl of the conserved threonine are shown. Note that different threonine rotamers form the hydrogen bonds to the acetate and oxygen. • Crystal structure of cytochrome P450 2B4 in complex with acetate • Two water molecules insert in the I-helix of the cytochrome P450 2B4 mutant active site • In cytochrome P450 2B4 acetate binds to the heme and side chain of Thr302. • The acetate bound active site of ferric cytochrome P450 2B4 resembles that of the oxygen bound P450 cam .

Binding Pattern Determination Of Class of Antifungal Drugs

AbstractCrystal Structure of cytochrome p450 2B4 has 476 amino acids, through docking approach we have attempted to explain the specificity of CYP2B4, total 28 imidazole drug were used for the studies as antifungal drugs in which bound bifonazole (reference) shows the binding energy of -8.67 kcal/mol .Compound Miconazole shows the minimum binding energy of -10.45 kcal/mol. The 2B4-bifonazole structure identified 10 residues (ALA 298, GLY 299, GLU 301, THR 302, ILE 363, VAL 292) within 6.5 Å of the active site of bifonazole. GLU 301, THR 302 are also located in 6.5 Å of the bound ligand in 2B4 structure. Due to the presence of the multiple binding substrates in cytochrome p450, it acts as the major target of many drugs in xenobiotic metabolism.

Conformational plasticity of cytochrome P450 2B4: crystallographic and solution studies

Cytochromes P450 are the most important oxidative enzymes involved in xenobiotic metabolism. Understanding the structural basis of P450-ligand interactions is a prerequisite for evaluating and predicting the metabolism of drugs. A crystal structure of cytochrome P450 2B4 bound with the antifungal drug bifonazole reveals an active site cleft that is widely open in the middle but narrow at the top. A bifonazole molecule occupies the bottom of the active site cleft where helix I is bent ~15° to accommodate the ligand. The O-shaped active site cleft of 2B4-bifonazole is very different from the previously determined structures of ligand-free 2B4 and 2B4 bound with the smaller inhibitor 4-(4-chlorophenyl)imidazole (CPI). Comparison of the three 2B4 structures identified structurally conserved regions and structurally flexible regions, providing new insight into structural plasticity of the enzyme. Isothermal titration calorimetry and fluorescence quenching experiments indicated that the conformation of 2B4-bifonazole is different from that of 2B4-CPI in solution. These results demonstrated that 2B4 can adopt strikingly different conformations in order to reshape its active site to accommodate ligands of different size. [Supported by National Institutes of Health grants ES03619 (to J.R.H.), GM61545 (to C.D.S.), and Center grant ES06676 (to J.R.H.)].