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Researchers have solved the mystery of the opposing effects—activation and inhibition—of two similar small organic molecules on bacterial heat-shock protein 70 (Hsp70), a molecular chaperone involved in protein folding and other cell functions.
The work, carried out by Jason Gestwicki of the University of Michigan, a specialist in multiprotein complexes, and coworkers, could lead to a better understanding of how Hsp70 works on the molecular level. New insights about Hsp70 are important because of its emerging roles in cancer, infection, and neurodegenerative disease. The work also provides a road map for obtaining contrasting biological effects from the same small-molecule chemical scaffold (ACS Chem. Biol., DOI: 10.1021/cb1000422).
Two years ago, Gestwicki’s group, in collaboration with two University of Pittsburgh groups led by chaperone expert Jeffrey L. Brodsky and organic synthesis specialist Peter Wipf, identified two small molecules that affect Hsp70. One molecule, called 115-7c, activates the chaperone, and the related compound, 116-9e, inhibits it, both in vitro and in living cells. The researchers were astonished that two similar small molecules could have such contradictory effects on the same system.
Now, Gestwicki and coworkers have used NMR, mutagenesis, and other techniques to understand how this happens. Surprisingly, the study shows that 115-7c and 116-9e bind at the same protein-protein interface—one formed when Hsp70 is bound by Hsp40, a “cochaperone” that regulates Hsp70’s activity.
Compound 115-7c binds at the Hsp40-Hsp70 interface and appears to cooperate with Hsp40 to activate Hsp70. The other agent, 116-9e, doesn’t activate the chaperone. Instead it blocks Hsp40-Hsp70 binding, effectively inhibiting the chaperone system.
It’s unusual to find druglike agents with any effect on protein-protein interfaces, which are generally too large to be disrupted by small molecules, but it’s unheard of for such similar chemical agents to have opposite effects. “We don’t know of any other examples” in which a single small-molecule scaffold such as the one shared by 115-7c and 116-9e affects a protein-protein interface in reverse ways, Gestwicki says.
Although the effects of the two chemical probes “are modest, they are very promising and may help identify novel allosteric sites that could eventually be structurally characterized to help develop more potent molecules,” says chemical biologist Charles S. Craik of the University of California, San Francisco, whose research interests include protein-protein interactions.
Compounds related to 116-9e are currently being tested for activity in mouse models of Alzheimer’s disease, Gestwicki says.
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