Abstract
The over two dozen CYP2B structures of human, rabbit, and woodrat enzymes solved in the last decade have significantly enhanced our understanding of the structure-function relationships of drug metabolizing enzymes. More recently, an important role has emerged for halogen-π interactions in the CYP2B6 active site in substrate selectivity, explaining in part the preference for halogenated ligands as substrates. The mechanism by which such ligands interact with CYP2B enzymes involves conserved phenylalanine side chains, in particular F108, F115, or F297, in the active site, which form π bonds with halogens. To illustrate such halogen-π interactions using drugs that are major substrates of CYP2B6, we present here a crystal structure of CYP2B6 in complex with an analog of the widely used anti-HIV drug efavirenz, which contains a methyl group in place of the carbonyl oxygen. The chlorine of the efavirenz analog forms a π bond with the aromatic ring of F108, whereas the putative metabolism site on the distal end of the molecule is oriented towards the heme iron. The crystal structure showcases how CYP2B6 accommodates this important drug analog of considerable size in the active site by movement of various side chains without substantially increasing the active site volume. Furthermore, the CYP2B6-efavirenz analog complex provides a useful platform to investigate computationally as well as biophysically the effect of genetic polymorphisms on binding of the widely studied efavirenz.
Highlights
The cytochrome P450 (CYP) enzymes found on the membrane of the endoplasmic reticulum are a superfamily of heme-containing monooxygenases involved in the biotransformation of drugs and other xenobiotics [1]
The functional differences observed among these enzymes, which include rat CYP2B1, rabbit CYP2B4, human CYP2B6, dog CYP2B11, and woodrat CYP2B35 and 37, have allowed in-depth exploration of structure-function relationships of direct relevance to drug metabolism by other CYP families [8]
We demonstrated the role of halogen-π interactions in CYP2B6 ligand orientation through the use of halogenated and non-halogenated monoterpenes [21]
Summary
The cytochrome P450 (CYP) enzymes found on the membrane of the endoplasmic reticulum are a superfamily of heme-containing monooxygenases involved in the biotransformation of drugs and other xenobiotics [1]. Out of the 57 human CYP enzymes, about a dozen are involved in drug metabolism, including enzymes from the CYP1, 2 and 3 families [2]. The functional differences observed among these enzymes, which include rat CYP2B1, rabbit CYP2B4, human CYP2B6, dog CYP2B11, and woodrat CYP2B35 and 37, have allowed in-depth exploration of structure-function relationships of direct relevance to drug metabolism by other CYP families [8]. CYP2B6 shares at least 75% amino acid sequence identity with other members of the subfamily, constitutes up to 10% of the functional CYP enzymes in human liver, and is responsible for the metabolism of 10–12% of all drugs currently available on the market [9]. Because of the relatively low-affinity binding of efavirenz itself, the 2-desoxo-2-methyl analog that demonstrated high-affinity binding (KS = 0.21 ± 0.06 μM) was used for the structural studies reported here. The efavirenz analog (efavirenz 2-desoxo-2-methyl) is abbreviated as I throughout the manuscript for convenience purposes
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