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 signals across the cell membrane to intracellular partner proteins, such as G proteins or ?-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 the GPCR superfamily. The proposed research directions are designed to accelerate high-resolution structure determination of membrane proteins, improve our understanding of the 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 integrates 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 GPCRs using the tools of structural biology, and to use the achieved insights to accelerate the design and development of novel and efficacious therapeutics.

Public Health Relevance

GPCR-mediated signaling pathways play a key role in all physiological systems as well as pathophysiological conditions including cancer, immune disorders, cardiovascular diseases, metabolic disorders (e.g. obesity, diabetes), pain and addiction. Over 30% of all prescription drugs on the market act via these receptors. The structural biology study of the human GPCR family will result in developing a deeper and more thorough understanding of molecular mechanisms of ligand recognition and receptor function, which should translate into development of more efficient therapeutics with diminished side effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM127086-03
Application #
9925243
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Preusch, Peter
Project Start
2018-05-01
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Southern California
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089