Generic placeholder image

Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Plasticity of CYP2B Enzymes: Structural and Solution Biophysical Methods

Author(s): P. Ross Wilderman and James R. Halpert

Volume 13, Issue 2, 2012

Page: [167 - 176] Pages: 10

DOI: 10.2174/138920012798918417

Price: $65

Abstract

In the past three years, major advances in understanding cytochrome P450 2B (CYP2B) structure-function relationships have been made through determination of multiple ligand-bound and one ligand-free X-ray crystal structure of CYP2B4 and one ligand-bound X-ray crystal structure of CYP2B6. These structures have provided insight into the features that provide the high degree of plasticity of the enzymes. A combination of a phenylalanine cluster that allows for concerted movement of helices F through G and a conserved set of electrostatic interactions involving Arg262 facilitates movement of this region to accommodate binding of ligands of various sizes without perturbing most of the P450 fold. Integrating solution based techniques such as NMR or deuterium exchange mass spectrometry (DXMS) with computational methods including molecular docking has provided further insight into enzyme behavior upon ligand binding. In addition, extended molecular dynamics simulations have provided a link between an open and a closed conformation of ligand-free CYP2B4 found in crystal structures. Other studies revealed the utility of rational engineering in improving stability of P450s to facilitate structural studies. The solution and computational results combined with the X-ray crystal structures yield a comprehensive picture of how these enzymes adopt different conformations to bind various ligands.

Keywords: Cytochrome P450, CYP2B, crystallography, NMR, deuterium exchange mass spectrometry, molecular modeling, molecular dynamics simulation, biotransformation, rational mutagenesis, ligand-bound complex


Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy