SC5: GPCR Structure-Based Drug Discovery

Monday, September 21, 12:00-3:00 pm

Recent breakthroughs in obtaining high resolution structures of G Protein-Coupled Receptors (GPCRs) are rapidly impacting the pharmaceutical industry. This course will review how newly elucidated GPCR crystal structures have informed our current understanding of GPCR function. Methodologies for GPCR crystallization will also be covered. The last third of the course will focus on the role of conformational dynamics in GPCR function and the structural biology techniques used for studying receptor dynamics, including the burgeoning field of nuclear magnetic resonance (NMR) applications.

Instructors (all are currently or formerly from the Laboratory of Ray Stevens):

Matthew Eddy, Ph.D., Postdoctoral Fellow, Ray Stevens Laboratory, University of Southern California

Wei Liu, Ph.D., Assistant Professor, Department of Chemistry and Biochemistry, Arizona State University

Huixian Wu, Ph.D., Postdoctoral Associate, Stuart Schreiber Laboratory, Center for the Science of Therapeutics, The Broad Institute

Detailed Outline:

Huixian Wu will cover: 

• Overview of GPCRs and their impact in the pharmaceutical industry 
• Review of GPCR structures and their lessons 

·         
Wei Liu will cover:

• Methodologies for the characterization and crystallization of GPCRs, including:
• LCP (Lipidic Cubic Phase) crystallization technique that solved over 20 GPCR structures  
• XFEL (X-Ray Free Electron Laser) method that handles small (sub-10-μm) crystals.

Matthew Eddy will cover:

• Role of conformational dynamics in GPCR function 
• Application of nuclear magnetic resonance (NMR) to study GPCR structure and dynamics 
• Review of recent studies of GPCR dynamics and their lessons 

Instructor Bios:

Matthew Eddy, Ph.D., Postdoctoral Fellow, Ray Stevens Laboratory, University of SoutherCalifornia

Dr. Matthew Eddy is a physical chemist who specializes in the investigation of the structure and conformational dynamics of membrane proteins, including G Protein-Coupled Receptors, using nuclear magnetic resonance (NMR). Dr. Eddy received his Ph.D. from the Massachusetts Institute of Technology, working in the laboratory of Professor Robert Griffin. During his Ph.D., Dr. Eddy developed new methodologies for applying solid state NMR to study the structure and dynamics of membrane proteins, focusing on discovering the mechanism of ion selectivity of the human mitochondrial membrane protein VDAC. After completing his Ph.D, Dr. Eddy joined the laboratory of Professor Ray Stevens at The Scripps Research Institute. There, he began working in collaboration with Professor Kurt Wüthrich to investigate the conformational dynamics of G Protein-Coupled Receptors with solution nuclear magnetic resonance. Dr. Eddy has authored or coauthored over 21 publications and is currently an American Cancer Society postdoctoral fellow in Professor Stevens’ laboratory at the University of Southern California.

Wei Liu, Ph.D., Assistant Professor, Department of Chemistry and Biochemistry, Arizona State University

In 2002, Wei received his B.Sc. from the Department of Biological Pharmacology from Wuhan University in China. Then he joined Dr. Martin Caffrey’s laboratory at Ohio State University. Following five years of graduate studies at Ohio State University, Wei moved on to Dr. Raymond Steven’s and Dr. Vadim Cherezov’s laboratory at the Scripps Research Institute (TSRI). At TSRI, Wei dedicated himself to continuous innovations on lipid cubic phase (LCP) technology, and successfully applied LCP technology to resolving the crystal structures of several important human G protein-coupled receptors (GPCR). Wei’s current research interest involves understanding receptor, mainly GPCR-mediated biological processes involved in cancer development.

Huixian Wu, Ph.D., Postdoctoral Associate, Stuart Schreiber Laboratory, Center for the Science of Therapeutics, The Broad Institute

Dr. Huixian Wu is interested in using x-ray crystallography to understand the structures of important drug target and its interaction with small molecule compounds, with particular specialization in membrane proteins. Dr. Wu received her Ph.D. in Structural Biology and Chemistry from The Scripps Research Institute (TSRI) working with Prof. Ray Stevens focusing on G Protein-Coupled Receptor (GPCR). While in Stevens laboratory, Dr. Wu determined the crystal structures of several important human GPCRs, including the kappa opioid receptor, the first class C GPCR, metabotropic glutamate receptor, the first class F GPCR, smoothened receptor, and authored multiple Nature and Science papers. Currently, Dr. Wu is a Post-doctoral Associate in Prof. Stuart L. Schreiber’s group in The Broad Institute (Cambridge, MA), working on structure-based drug discovery targeting the inflammatory bowel diseases.

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