2011
DOI: 10.1124/dmd.111.039719
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Structure and Function of Cytochromes P450 2B: From Mechanism-Based Inactivators to X-Ray Crystal Structures and Back

Abstract: ABSTRACT:This article reviews work from the author dating back to 1978 and focuses on the structural basis of cytochrome P450 (P450) function using available contemporary techniques. Early studies used mechanism-based inactivators that bound to the protein moiety of hepatic P450s to try to localize the active site. Subsequent studies used cDNA cloning, heterologous expression, site-directed mutagenesis, and homology modeling based on multiple bacterial P450 X-ray crystal structures to predict the active sites … Show more

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Cited by 29 publications
(34 citation statements)
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“…The structural overlay of CYP2A6 and CYP2B6 in complex with sabinene resulted in an RMSD of ∼0.78 Å (Fig. 3A), which is slightly larger than the RMSD observed between CYP2B4 and CYP2B6 in complex with either 4-CPI (0.65 Å) or amlodipine (0.66 Å) (Halpert, 2011;Shah et al, 2012), and CYP2A6 and CYP2A13 with pilocarpine (0.63 Å) . However, the sequence identity between CYP2A6 and CYP2B6 is only 51%, which is significantly less than that between CYP2B4 and CYP2B6 (78%) or CYP2A6 and CYP2A13 (94%), suggesting that the ability to conform to these ligands outweighs sequence differences in the amino acid sequences of CYP2B6 and CYP2A6.…”
Section: Comparison Of Cyp2b6 and Cyp2a6 Structures Inmentioning
confidence: 83%
“…The structural overlay of CYP2A6 and CYP2B6 in complex with sabinene resulted in an RMSD of ∼0.78 Å (Fig. 3A), which is slightly larger than the RMSD observed between CYP2B4 and CYP2B6 in complex with either 4-CPI (0.65 Å) or amlodipine (0.66 Å) (Halpert, 2011;Shah et al, 2012), and CYP2A6 and CYP2A13 with pilocarpine (0.63 Å) . However, the sequence identity between CYP2A6 and CYP2B6 is only 51%, which is significantly less than that between CYP2B4 and CYP2B6 (78%) or CYP2A6 and CYP2A13 (94%), suggesting that the ability to conform to these ligands outweighs sequence differences in the amino acid sequences of CYP2B6 and CYP2A6.…”
Section: Comparison Of Cyp2b6 and Cyp2a6 Structures Inmentioning
confidence: 83%
“…At the core of P450 enzymes is a porphyrin heme, locked in place by electrostatic interactions with a number of conserved arginine residues and a ring of hydrophobic amino acids that sandwich the heme against the rigid, conserved I helix Yano et al, 2004;Sansen et al, 2007;Halpert, 2011;Shah et al, 2011). Positioning the I helix of each P450 parallel to the z-axis, each of the isoforms was divided into four quadrants to explore the location of the cysteine residues (Fig.…”
Section: Discussionmentioning
confidence: 99%
“…Dynamic relationships between the loop-like structures that form the substrate binding cavity enable adaptations that open and close solvent access channels to facilitate access to and egress from the active site for solvent molecules, substrates, inhibitors, and products (Cojocaru et al, 2007) and that facilitate adaptations to accommodate structurally diverse drugs (Wester et al, 2003;Ekroos and Sjogren, 2006;Halpert, 2011). These adaptations can be important for positioning the substrate near the reactive intermediate and prolongation of residency during the reaction cycle.…”
Section: Introductionmentioning
confidence: 99%