Molecular model of predicted interaction sites for compounds M201 and M119 with G protein βγ subunits. Both of the compounds modify G protein function but M201 on the left has a different set of actions than M119 on the right. We hypothesize that these two compounds have different effects because they bind to different regions of the "hot spot". Libraries of compounds could be discovered that modify pharmacological efficacy and potency in many different and selective ways, based on this principle.
A major effort in the laboratory is directed at understanding mechanisms for regulation of signal transduction by G protein βγ subunits. Beta-gamma subunits interact directly with a wide variety of target enzymes, ion channels, and regulatory proteins and have been found to play critical roles in various aspects of metabolism and cell growth.
A major hypothesis of the lab is that each binding partner for beta-gamma subunits has a unique mode of binding to βγ subunits and that this could be exploited pharmacologically to develop specific inhibitors. We want to define these unique modes of interaction both on the basis of sequence and structure and to exploit this knowledge to understand cellular physiology.
1) Pharmacological development. One project is directed at mapping the binding sites on βγ subunits for binding of target molecules. We are using a combination of mutagenesis and chemical crosslinking to map critical regions of effector binding on the surface of βγ subunits.
2) Cell physiology. We are exploiting some of the pharmacological tools that we have developed to study specific roles of beta-gamma subunits in the cardiovascular system. In particular, we are interested in the roles of βγ signaling in cardiac hypertrophy and in vascular remodeling.
3) Whole animal physiology. We are exploiting some of the pharmacological tools that we have developed to study specific roles of βγ subunits in the cardiovascular system and the brain. In particular, we are interested in the roles of βγ signaling in cardiac hypertrophy and morphine dependent antinociception.
Alan V. Smrcka, Ph.D.
University of Rochester
School of Medicine and Dentistry
601 Elmwood Avenue
Rochester, NY 14642