5WBG

Crystal Structure of human Cytochrome P450 2B6 (Y226H/K262R) in complex with an analog of a drug Efavirenz

5WBG の概要

• エントリーDOI: 10.2210/pdb5wbg/pdb
• 関連するPDBエントリー: 3UA5 4I91 5UAP 5UDA 5UEC
• 分子名称: Cytochrome P450 2B6, PROTOPORPHYRIN IX CONTAINING FE, (2R,4S)-6-chloro-4-(cyclopropylethynyl)-2-methyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine, ... (6 entities in total)
• 機能のキーワード: oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 336112.41

構造登録者

Shah, M.B.,Halpert, J.R. (登録日: 2017-06-29, 公開日: 2018-05-02, 最終更新日: 2023-10-04)

主引用文献

Shah, M.B.,Zhang, Q.,Halpert, J.R.
Crystal Structure of CYP2B6 in Complex with an Efavirenz Analog.
Int J Mol Sci, 19:-, 2018

PubMed 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.

PubMed: 29596329
DOI: 10.3390/ijms19041025

実験手法

X-RAY DIFFRACTION (2.99 Å)