Discovery of a Shape Shifting Protein Could Lead to Anti-Bacterial Agent

Eileen K. Jaffe, Ph.D.
Institute for Cancer Research
Fox Chase Cancer Center
NIEHS Grant R01ES003654-24

A small molecule that locks the shape of the enzyme porpholbilinogen synthase (PBGS) into an inactive form could one day form the basis of a new species specific antibiotic, according to NIEHS-supported researchers at the Fox Chase Cancer Research Laboratory.

PBGS is crucial for energy metabolism in nearly all organisms. To be activated, it must have two subunits added to the six-subunit molecule, or hexamer configuration, which makes up its basic form. Without this addition, the enzyme remains inactive. The research team discovered a small molecule, Morphlock-1, which binds to the inactive form of the enzyme and locks the enzyme in a hexamer shape; thus preventing the rearrangement of the molecule and the addition of the two additional subunits required for activation.

While this study utilized a form of the enzyme found in peas, the researchers believe that this principle could apply to bacterial versions of the enzyme as well. Current research is aimed at fine tuning the structure of Morphlock-1 so that it blocks just the bacterial version of the enzyme and not other cells. They are taking advantage of the fact that the small molecule binds to other species’ versions of the enzyme in different locations. Morphlock-1 in its current configuration does not bind the PBGS enzyme from humans, fruit flies, or bacterial sources.

Multidrug resistance drives the need for developing new antibiotics. The researchers are confident they will be able to find a structure of the molecule or perhaps new molecules that will bind the bacterial version of the enzyme and render it completely inactivated; therefore causing the bacteria to die. They hope to develop a suite of drugs that will stabilize the PBGS hexamer in order to prevent bacteria from developing complete resistance to a cocktail of such compounds.

Citation: Lawrence SH, Ramirez UD, Tang L, Fazliyez F, Kundrat L, Markham GD, Jaffe EK. Shape shifting leads to small-molecule allosteric drug discovery. Chem Biol. 2008 Jun;15(6):586-96.