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

The paper:

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)

The finding:

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.

The challenge:

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...

The significance:

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.

The next steps:

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.

Enzyme structural change
Unbound Ketoconazole Erythromycin
Alpha Carbon bond length shift n/a 3.1 Å 2.8 Å
Active site volume 950 Å3 1,650 Å3 2,000 Å3

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