Our laboratory is primarily interested in the elucidation of the molecular mechanism my 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.
The diversity of this family of 7 transmembrane domain proteins and their importance in cellular signaling make GPCRs optimal targets for therapeutics. Indeed, the majority of all therapeutics currently marketed target this family of membrane-bound receptors. The development of more efficacious and selective therapeutics that target GPCRs continues to be a major effort in the pharmaceutical industry. A detailed understanding of the function and structure of hormone and therapeutic binding sites will lead to the development of more potent and selective therapeutics.
Advances in structural biology have resulted in the elucidation of the atomic structures of thousands of cytosolic proteins. Together with a plethora of functional data a firm understanding of how these proteins work has been appreciated. Unfortunately only a hundred or so membrane protein structures have been resolved. The structure a handful of GPCRs, including the beta1 and beta2-adrenergic receptors and the photorreceptor rhodopsin, have been elucidated thus far. These monumental achievements reveal the nature of the hormone binding site or the position of the chromophore in atomic detail. While these data have provided the framework for how ligands bind to GPCR, or how light induces isomerization of the chromophore, little is know about how GPCRs activate G proteins.
In addition, high-resolution structural and functional data of other GPCRs by themselves or in complex with G proteins remain as a priority in the signaling field. Knowledge of the three-dimensional structures of the chemokine receptors, the known GPCRs and co-receptors for HIV could lead to the development of selective drugs that block HIV infection. Knowledge of the structure of opioid receptor may aid in the development of more selective and potent analgesics. Moreover, most neuroleptics target the dopamine D2 family of receptors, also GPCRs, are used for the treatment of schizophrenia, Huntington’s Chorea and Parkinson’s Syndrome. The development of more selective dopamine receptor ligands, with reduced side-effects, will improve drug efficacy, improve drug compliance and most of all improve the quality of life during treatment.
