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) - which metabolizes about 50% of drugs on the market - by presenting 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 ...
