The structure of the cytochrome p450BM-3 haem domain complexed with the fatty acid substrate, palmitoleic acid

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Abstract

The substrate-bound structures of two cytochrome P450s, P450cam and P450eryF, are known. While these structures reveal important features that control substrate specificity, the problem of how conformational changes allow for substrate entry and product release remains unsolved. The structure of the haem domain of the bacterial fatty acid hydroxylase, P450BM-3, previously was solved in the substrate-free form. Unlike the substrate-bound P450cam and P450eryF structures, the substrate access channel is open in substrate-free P450BM-3. Here we present the X-ray structure of P450BM-3 at 2.7 A bound with a fatty acid substrate, palmitoleic acid. A comparison of the substrate-bound and -free forms reveals major conformational differences and provides the first detailed picture of substrate-induced conformational changes in a P450.

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Most cited references 19

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J. Navaza (1994)

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High-resolution crystal structure of cytochrome P450cam.

T L Poulos, B. Finzel, A Howard (1987)

The crystal structure of Pseudomonas putida cytochrome P450cam with its substrate, camphor, bound has been refined to R = 0.19 at a normal resolution of 1.63 A. While the 1.63 A model confirms our initial analysis based on the 2.6 A model, the higher resolution structure has revealed important new details. These include a more precise assignment of sequence to secondary structure, the identification of three cis-proline residues, and a more detailed picture of substrate-protein interactions. In addition, 204 ordered solvent molecules have been found, one of which appears to be a cation. The cation stabilizes an unfavorable polypeptide conformation involved in forming part of the active site pocket, suggesting that the cation may be the metal ion binding site associated with the well-known ability of metal ions to enhance formation of the enzyme-substrate complex. Another unusual polypeptide conformation forms the proposed oxygen-binding pocket. A localized distortion and widening of the distal helix provides a pocket for molecular oxygen. An intricate system of side-chain to backbone hydrogen bonds aids in stabilizing the required local disruption in helical geometry. Sequence homologies strongly suggest a common oxygen-binding pocket in all P450 species. Further sequence comparisons between P450 species indicate common three-dimensional structures with changes focused in a region of the molecule postulated to be associated with the control of substrate specificity.

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SETOR: hardware-lighted three-dimensional solid model representations of macromolecules.

Stephen Evans (1993)

SETOR is designed to exploit the hardware lighting capabilities of the IRIS-4D series graphics workstations to render high-quality raster images of macromolecules that can undergo rotation and translation interactively. SETOR can render standard all-atom and backbone models of proteins or nucleic acids, but focuses on displaying protein molecules by highlighting elements of secondary structure. The program has a very friendly user interface that minimizes the number of input files by allowing the user to interactively edit parameters, such as colors, lighting coefficients, and descriptions of secondary structure via mouse activated dialogue boxes. The choice of polymer chain representation can be varied from standard vector models and van der Waal models, to a B-spline fit of polymer backbones that yields a smooth ribbon that approximates the polymer chain, to strict Cardinal splines that interpolate the smoothest curve possible that will precisely follow the polymer chain. The program provides a photograph mode, save/restore facilities, and efficient generation of symmetry-related molecules and packing diagrams. Additionally, SETOR is designed to accept commands and model coordinates from the standard input stream, and to control standard output. Ancillary programs provide a method to interactively edit hardcopy plots of all vector and many solid models generated by SETOR, and to produce standard HPGL or PostScript files. Examples of figures rendered by SETOR of a number of macromolecules of various classes are presented.