Structure of human microsomal cytochrome P450 2C8. Evidence for a peripheral fatty acid binding site.

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Schoch GA, Yano JK, Wester MR, Griffin KJ, Stout CD, Johnson EF

Structure of human microsomal cytochrome P450 2C8. Evidence for a peripheral fatty acid binding site.

J Biol Chem. 2004 Mar 5;279(10):9497-503. Epub 2003 Dec 15.

PubMed ID

14676196 [ View in PubMed

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Abstract

A 2.7-Angstrom molecular structure of human microsomal cytochrome P450 2C8 (CYP2C8) was determined by x-ray crystallography. The membrane protein was modified for crystallization by replacement of the hydrophobic N-terminal transmembrane domain with a short hydrophilic sequence before residue 28. The structure of the native sequence is complete from residue 28 to the beginning of a C-terminal histidine tag used for purification. CYP2C8 is one of the principal hepatic drug-metabolizing enzymes that oxidizes therapeutic drugs such as taxol and cerivastatin and endobiotics such as retinoic acid and arachidonic acid. Consistent with the relatively large size of its preferred substrates, the active site volume is twice that observed for the structure of CYP2C5. The extended active site cavity is bounded by the beta1 sheet and helix F' that have not previously been implicated in substrate recognition by mammalian P450s. CYP2C8 crystallized as a symmetric dimer formed by the interaction of helices F, F', G', and G. Two molecules of palmitic acid are bound in the dimer interface. The dimer is observed in solution, and mass spectrometry confirmed the association of palmitic acid with the enzyme. This novel finding identifies a peripheral binding site in P450s that may contribute to drug-drug interactions in P450 metabolism.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Palmitic Acid	Cytochrome P450 2C8	Protein	Humans	Unknown	Not Available	Details

Polypeptides

Name	UniProt ID
Cytochrome P450 2C8	P10632	Details