Protein Engineering, Vol 10, 119-129, Copyright © 1997 by Oxford University Press
YT Chang, OB Stiffelman, IA Vakser, GH Loew, A Bridges and L Waskell
A three-dimensional structural model of rabbit phenobarbital-inducible
cytochrome P450 2B4 (LM2) was constructed by homology modeling techniques
previously developed for building and evaluating a 3D model of the
cytochrome P450choP isozyme. Four templates with known crystal structures
including cytochrome P450cam, terp, BM-3 and eryF were used in multiple
sequence alignments and construction of the cytochrome P450 2B4
coordinates. The model was evaluated for its overall quality using
available protein analysis programs and found to be satisfactory. The model
structure was stable at room temperature during a 140 ps unconstrained full
protein molecular dynamics simulation. A putative substrate access channel
and binding site were identified. Two different substrates, benzphetamine
and androstenedione, that are metabolized by cytochrome P450 2B4 with
pronounced product specificity were docked into the putative binding site.
Two orientations were found for each substrate that could lead to the
observed preferred products. Using a geometric fit method three regions on
the surface of the model cytochrome P450 structure were identified as
possible sites for interaction with cytochrome b5, a redox partner of P450
2B4. Residues that may interact with the substrates and with cytochrome b5
have been identified and mutagenesis studies are currently in progress.
ARTICLES
Construction of a 3D model of cytochrome P450 2B4
Molecular Research Institute, Palo Alto, CA 94304, USA.
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