2013 Archived Content


GPCR-Based Drug Design

Computational and Structural Approaches

April 17-18, 2013

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7:30 am Breakfast Workshop Presentation (Sponsorship Opportunity Available) or Morning Coffee

Probing GPCR Structure 

8:15 Chairperson’s Opening Remarks

Ruben Abagyan, Ph.D., Professor, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego


Structure of the Agonist-Bound Neurotensin Receptor NTS1

Reinhard Grisshammer, Ph.D., Investigator, National Institute of Neurological Disorders and Stroke (NINDS), NIH

Neurotensin is a peptide that functions as both a neurotransmitter and a hormone through activation of the neurotensin receptor NTS1, a G protein-coupled receptor (GPCR). I will present the structure at 2.8 Å resolution of NTS1 in an active-like state, bound to the peptide agonist. Our findings provide for the first time insight into the binding mode of a peptide agonist to a GPCR.

9:00 High-Resolution Structure of Human Adenosine A2A Receptor Reveals Allosteric Binding Sites for Sodium Ion and Cholesterols

Vadim Cherezov, Ph.D., Assistant Professor, Department of Molecular Biology, The Scripps Research Institute

1.8 A resolution structure of adenosine A2A receptor revealed a Na+ ion, 177 waters, 3 cholesterols and 26 lipids. Such unprecedented high-resolution details help to shed light on the role of waters in ligand binding and receptor activation, and to understand the allosteric effects of sodium, cholesterol and lipids on GPCR function.

9:30 Identifying an Alternate Antagonist Binding Site for a Diabetes Target: A GPCR Case Study

Carleton Sage, Ph.D., Fellow, Computational Systems, Arena Pharmaceuticals

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

10:45 Probing Receptor Signaling Using Genetically-Encoded Unnatural Amino Acids

Thomas P. Sakmar, M.D., Professor, Laboratory of Chemical Biology & Signal Transduction, The Rockefeller University

Recent advances in molecular and structural studies of GPCRs have revolutionized drug discovery. Our aim is to elucidate the principles that underlie ligand recognition in GPCRs and to understand with chemical precision how receptors change conformation in the membrane bilayer when ligands bind. This lecture will describe new interdisciplinary technologies to study receptor dynamics and allosteric mechanisms.

11:15 Nanobodies for the Structural and Functional Investigation of GPCR Transmembrane Signaling

Jan Steyaert, Ph.D., Executive Director and Professor, Molecular and Cellular Interactions, Vrije Univ Brussels

We generated Nanobodies that stabilize transient functional conformations of the human β2 adrenergic receptor. Nanobodies that faithfully mimic G protein binding were used to crystallize active agonist-bound states of this GPCR. Other nanobodies that stabilize the β2AR•Gs complex were instrumental to obtain the crystal structure of this complex, providing the first view of transmembrane signaling by a GPCR.

11:45 Structural Insights into Muscarinic Acetylcholine Receptor Function

Andrew C. Kruse, Graduate Student, Brian Kobilka (2012 Nobel Laureate) Lab, Department of Molecular and Cellular Physiology, Stanford University

I will present the recently determined structures of two muscarinic acetylcholine receptors, which offer new insight into ligand selectivity and allosteric modulation of muscarinic receptors and of GPCRs in general. In addition, I will discuss more recent work toward understanding the ligand binding and activation of these important receptors.

12:15 pm Sponsored Presentation (Opportunity Available)

12:30 Walk and Talk Luncheon in the Exhibit Hall (Last Chance for Poster and Exhibit Viewing)

Computational Approaches 

1:55 Chairperson’s Remarks

Carleton Sage, Ph.D., Fellow, Computational Systems, Arena Pharmaceuticals

2:00 From GPCR Structure to Predictive Models

Ruben Abagyan, Ph.D., Professor, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego

As the number of GPCRs with known crystal structure approaches fifteen, the opportunities for structure based understanding of their function grow dramatically. Here we present the challenges and successes in predicting how orthosteric and allosteric ligands bind to GPCRs, as well as how protein and peptide ligands bind to family A and family B GPCRs.

2:30 Computational Approaches to GPCRs

Christopher A. Reynolds, Ph.D., MRC Fellow, Professor, School of Biological Sciences, University of Essex

Homology models of the calcitonin receptor-like receptor, a medically important class B GPCR; were constructed using a novel approach to the alignment and validated using experiment and theory. Distinct class B motifs and their class A equivalents have been identified. The relevance to drug design is discussed.

3:00 Hydrogen/Deuterium Exchange Captures Subtle Conformation Changes to GPCRs Upon Orthosteric Binding

Graham West, Ph.D., Postdoctoral Associate, Molecular Therapeutics, The Scripps Research Institute, Scripps Florida

Using hydrogen/deuterium exchange (HDX) coupled to mass spectrometry, we characterized conformation changes to the beta-2-adrenergic receptor in the presence of orthosteric ligands and absence of allosteric modulators (i.e. G proteins). Shifts to active GPCR conformations by orthosteric ligands alone have not been detected using crystallography. This work provides structural insight into GPCR signaling and presents a potential platform to structurally characterize GPCR-ligand interactions independent of tissue type.

3:30 Molecular Mechanisms of Vascular Alpha2C-adrenoreceptor Translocation

Marcin Pawlowski, Ph.D., Post-doctoral Scientist, Mathematical Medicine, The Research Institute at Nationwide Children's Hospital, Ohio

Alpha2C, a G protein-coupled receptor, has been recently found to act as a stress receptor of the vascular sympathetic system. Emerging evidence implicates this receptor in peripheral vascular conditions of Raynaud’s phenomenon [1-4]. Based on preliminary studies, we hypothesize that the last 14 amino acids of Alpha2C carboxyl terminus mediate interaction with filamin-2. In the absence of a crystal structure for α2C-AR and filamin-2 region, we utilized amino acid homology searches, domain predictions, followed by protein-protein docking, to identify the residues that play a key role in Alpha2C-filamin-2 recognition and binding. This bioinformatics approach identified arginines R-454, R456, R-461 (within the arginine-rich region) and lysine 449 to be stabilized by negatively charged residues within the filamin-2 structure: E2004, E2059, D2060, and aspartic acid at position 2032, respectively

4:00 End of Conference

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