Berkeley -- While most people may have difficulty distinguishing a person from his or her mirror image, proteins in cells have no such problem. They are exquisitely selective, able to latch on tightly to one molecule but reject its mirror image.
Now scientists claim that a 50-year-old theory explaining how proteins and enzymes discriminate so precisely, considered gospel by most researchers, needs revision.
The finding could significantly help drug designers, who may needlessly be discarding good drug candidates because of this misconception.
"The reigning theory of how enzymes distinguish between very slight differences in molecules is the three-point attachment model found in essentially all biochemistry textbooks," said Daniel E. Koshland Jr., professor of molecular and cell biology at the University of California, Berkeley, and a researcher in the Center for Advanced Materials at Lawrence Berkeley National Laboratory.
"This is very important in pharmacology, where drug designers rely on the theory to design a particular mirror image, or enantiomer, to fit exactly into the active site of an enzyme or receptor. Well, the classic explanation needs correction."
In a paper in the Feb. 10 issue of Nature, Koshland and Andrew D. Mesecar, a former postdoctoral fellow at UC Berkeley and now an assistant professor in the Department of Medicinal Chemistry and Pharmacognosy and the Center for Pharmaceutical Biotechnology at the University of Illinois, Chicago, argue that the so-called Ogsdon three-point attachment model must be replaced by a new four-point location model.
These models explain how proteins bind to "chiral" molecules, that is, molecules that cannot be superimposed on their mirror image. Typically the mirror-image versions of chiral molecules act very differently in the body. Some bacteria can degrade one version of a pollutant but not its mirror image; a key receptor in the brain is turned on by an amino acid but not its m
Contact: Robert Sanders
University of California - Berkeley