Crystal Structure of Variant P450 Determined
James R. Halpert, Ph.D.
University of California San Diego
NIEHS Grant R01ES003619
The crystal structure of a genetic variant of cytochrome P450 2B6 in complex with its inhibitor has been determined by an NIEHS grantee at the University of California San Diego. Structural insights like this are critical to understanding how the enzymes bind to substrates and metabolize compounds, and how different genetic variations affect the enzyme’s ability to initiate metabolism.
The multiple forms of cytochromes P450 metabolize a wide variety of endogenous and exogenous chemicals including prostaglandins, steroids, drugs, and environmental chemicals. P450s interact with a variety of substrates, inhibitors, membrane lipids and proteins that modulate their activity. P450s are heme-containing monoxygenase enzymes.
Genetic differences in the expression levels or activities of P450s are major determinants of individual responses to medications and environmental toxicants. This finding provides the first view of an important human enzyme that has been gaining in significance as the list of compounds it interacts with has grown.
Citation: Gay SC, Shah MB, Talakad JC, Maekawa K, Roberts AG, Wilderman PR, Sun L, Yang JY, Huelga SC, Hong WX, Zhang Q, Stout CD, Halpert JR. Crystal Structure of a Cytochrome P450 2B6 Genetic Variant in Complex with the Inhibitor 4-(4-Chlorophenyl)imidazole at 2.0 A Resolution. Mol Pharmacol. 2010 Jan 8.
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