FEB 21, 2018 9:00 AM PST

New Tools for Understanding Allosteric Signaling in G Protein Coupled Receptors

Presented at: Drug Discovery 2018
Speaker
  • Postdoctoral Research Fellow, The Scripps Research Institute
    Biography
      Matthew Eddy received his PhD in physical chemistry from the Massachusetts Institute of Technology in the laboratory of Professor Robert Griffin. During his PhD, Dr. Eddy developed new approaches for using nuclear magnetic resonance (NMR) in the solid state to determine structures of membrane proteins in cellular-like environments. Following his PhD, Dr. Eddy joined the laboratories of Professors Raymond Stevens and Kurt Wüthrich at The Scripps Research Institute as an American Cancer Society Postdoctoral Fellow. As a postdoctoral fellow, Dr. Eddy used an integrative structural biology approach to study the structures, conformational dynamics, and functions of human G protein-coupled receptors (GPCRs), focusing on the application of nuclear magnetic resonance to improve our understanding of GPCR allosteric function.

    Abstract

    One-third of FDA-approved drugs target G protein-coupled receptors (GPCRs), transmembrane cell surface proteins that recognize small molecules and polypeptides with diverse chemical scaffolds.  When a drug binds to the GPCR extracellular cavity, the information is communicated over 30 Ŭ¬¬ through the plasma membrane to the receptor intracellular surface, inducing changes in the receptor structure that enable complex formation with intracellular partner proteins.  Over the past decade, x-ray crystallography has revealed the three-dimensional structures and binding modes of a growing number of unique GPCR-ligand complexes.  To better understand mechanisms of GPCR activation, this information must be complemented by knowledge of dynamic signaling pathways connecting drug-binding sites to the intracellular surface.  Here we present the development of novel approaches that reveal GPCR signaling pathways with nuclear magnetic resonance (NMR) spectroscopy in solution.  Specific applications of this approach are described for the human A2A adenosine receptor (A2AAR), where NMR uncovers the role of a key allosteric center in drug-induced signal transduction.  Finally, I will discuss the potential extension of these findings and of the presented methods toward studies of other human GPCRs.


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