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Assistant Professor of Pharmacology
Our laboratory is primarily interested in the elucidation of the molecular mechanism by which hormones activate G Protein-Coupled Receptors (GPCRs). We utilize biochemical and biophysical approaches to delineate how hormone binding to these cell surface receptors leads to activation of G proteins. G protein-coupled receptors represent the largest family of membrane proteins in the human genome and the third largest family of genes overall. Their diversity has made GPCRs the target for greater than 30% of all therapeutics currently on the market. High-resolution structural and functional analyses of members of the GPCR superfamily will undoubtedly lead to the development of more efficient, more selective and more efficacious therapeutics. We have recently elucidated the crystal structure of the b2-adrenergic receptor (b2AR) in several conformations, including bound to its cognate G protein, Gs. The b2AR is a prototypical GPCR and the target of therapeutics used to treat many cardiovascular and smooth muscle ailments. The b2AR couples to the stimulatory G protein, Gs, which directly activates adenylyl cyclase, the enzyme that converts ATP to cAMP. Increases in the second messenger cAMP leads to activation of protein kinase A (PKA) among others and modulation of several downstream signaling cascades, including those that regulate transcription of thousands of genes.
The elucidation of the structure of the GPCR•G protein complex, in particularly, has revealed several novel aspects of G protein structure and function and thus opened up new areas in G protein signaling. Moreover this novel structural information has for the first time revealed the structure of the activated state a GPCR, a conformation that is induced, or rather stabilized, by agonists such as hormones. Together these data will provide a new framework with which the design and development of therapeutics may be based.
The goal of our laboratory is to utilize biophysical and biochemical approaches to elucidate the behavior of GPCRs and to determine how receptor conformation may influence the capacity to interact with intracellular signaling partners. Indeed G proteins represent a major signaling partner for GPCRs however these seven transmembrane domain-containing proteins also potently and actively recruit scaffolding proteins such as arrestins. In addition to being involved in receptor internalization and desensitization arrestins serve as scaffolding templates to recruit protein kinases including MEKs and Src. The recruitment of these complexes leads to activation of transcription through the ERK pathway. Most agonists and hormones activate both the arrestin and G protein signaling cascades. However, an intriguing phenomena surrounds the capacity of some ligands to stabilize a conformation that recruits arrestin but do not activate G protein-mediated signaling events. Conversely, there are collections of ligands that potently regulate G protein signaling but do not recruit arrestins. Thus, the study of the molecular bases of the behavior of these ‘biased ligands’ is a major priority in the GPCR field and a major component of our laboratories research interests. It is our aim to utilize biophysical and biochemical approaches to delineate the pharmacological properties of these biased ligands.
Chemistry BuildingRoom 4028930 N. University Ave.
Ann Arbor, MI