Elastic enzyme

Proc Natl Acad Sci, 103:13682-7, 2006 / ® 2006 National Academy of Sciences, U.S.A

M. Ekroos and T. Sjögren, "Structural basis for ligand promiscuity in cytochrome P450 3A4," Proc Natl Acad Sci, 103:13682-7, 2006. (Cited in 78 papers)

Researchers at AstraZeneca in MöIndal, Sweden, showed the flexible structure of enzyme cytochrome P450 3A4 (CYP3A4) -ﾠwhich metabolizes about 50% of drugs on the marketﾠ- byﾠpresenting crystal structures of it bound to two very different drugs, ketoconazole and erythromycin. The volume of the enzyme's active site, where the drugs are metabolized, increased more than 80 % after binding the drugs.

Although researchers had suspected that the enzyme underwent major shape-shifting when binding to various drugs, "previous attempts to obtain a structure with a ligand bound to the active site had failed," writes lead author Tove Sjögren in an E-mail. "The trick was to identify conditions where the ligand-bound form was more stable."

Given the structural flexibility of the enzyme during binding, it may be able to metabolize drugs in more ways than originally thought, says Anthony Lu, professor of chemical biology at Rutgers University.

Because CYP3A4 drug metabolism can cause side effects in the liver and small intestine, Sjögren's group is continuing to work on the enzyme's structure bound to different drugs.