Structural Biology Of G Protein-Coupled Receptors

Project Summary G protein-coupled receptors (GPCRs) constitute the largest membrane protein superfamily in the human genome, with over 800 unique sequences. GPCR-mediated signaling pathways play a key role in all physiological systems as well as many pathophysiological conditions and therefore represent important drug targets. GPCRs have a seven-transmembrane-helix (7TM) topology and contain multiple binding sites for orthosteric ligands and allosteric modulators. Upon recognition of their native ligands receptors transmit signal across the cell membrane to intracellular partner proteins, such as G proteins or β-arrestins. Developing a detailed understanding of functional mechanisms of GPCRs and facilitating design of novel drugs with high selectivity and potency require access to high-resolution three-dimensional structures, determination of which, however, remains a challenging task. We propose here a comprehensive research program which combines technology development with integrated structure-function studies focused on GPCR superfamily. The proposed research directions are designed to accelerate high-resolution structure determination of membrane proteins, improve our understanding of GPCR superfamily and answer specific questions on ligand specificity and selectivity as well as molecular mechanisms of action using several specific receptors as targets. Our approach integrate structural information on new receptors and complexes with data obtained from biophysical, biochemical and functional experiments through computer-based analysis and modeling. The long-term goal of our laboratory is to develop a deeper understanding of the molecular mechanisms of action of GPCR using the tools of structural biology and to apply the achieved insights towards the design and development of novel and efficacious therapeutics.