John Sondek

PhD, Pharmacology, UNC-Chapel Hill, Molecular Therapeutics

UNC-Chapel Hill
Molecular Therapeutics

Area of interest

Our laboratory studies signal transduction systems controlled by heterotrimeric G proteins as well as Ras-related GTPases. The superfamily of GTPases control numerous signaling cascades based upon the regulated binding, hydrolysis, and exchange of guanine nucleotides; GTP-bound GTPases are active in downstream signaling while those bound to GDP are inactive. Mutant GTPases with abnormal GDP/GTP cycling are implicated in numerous human diseases, including cancer. It is our desire to better understand the regulation of heterotrimeric G proteins and Ras-related GTPases at the molecular level with the ultimate goal of using this information to design therapies to correct abnormal signaling mediated by these proteins and thereby treat associated pathologies.

Awards and Honors

1. We determined the first atomic resolution structures of Rho GTPases engaging Dbl-family GEFs. These structures provide high-resolution “snapshots” of the activation of process of Rho GTPases and are being used to design small molecules to inhibit the constitutive activation of Rho GTPases. This work was featured by national news services and, of all places, Popular Mechanics.
2. Our lab was award a program project grant by the NIH to integrate our diverse research avenues in order to more efficiently studies signaling cascades controlled by heterotrimeric G protein and small GTPases. Aberrant control by these types of proteins routinely promotes cancer.
3. In collaboration with the laboratory of Dr. David Siderovski, we provided the first atomic-resolution structure of a heterotrimeric G protein alpha subunit bound to a GoLoco domain. The interaction of Ga subunits with GoLoco domains is an emerging area of understanding that falls outside our canonical framework of G proteins modulated by G protein-coupled receptors. More specifically,
GoLoco domains in proteins most likely allow for the modulation of these proteins by Ga-GDP subunits. This work is featured on the cover of the April 2002 issue of Molecular Interventions published by the American Society for Pharmacology and Experimental Therapeutics.

In 1999, was named a Pew Scholar in the Biomedical Sciences.

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