Project

Discipline

G protein-coupled receptors; GPCR signaling complex; Ligand specificity; Subtype localization; Mental disease; signaling; drug design

Lead
Lay summary
G protein-coupled receptors (GPCRs) are the target for pharmacological intervention by about 30% of medical drugs. As a consequence a detailed understanding of this protein class can assist in the development of better drugs with large benefits for human health. From a more fundamental, scientific point of view, GPCRs provide the principal sensors for our taste, smell and sight and are central to how we perceive our environment. About 800 genes in the human genome encode for GPCRs, reflecting the large number of physiological functions they are involved in. Despite this physiological and pharmacological relevance, the structural basis of how GPCRs are activated and how this translates into a cellular response remains largely elusive. In the Laboratory for Biomolecular Research at the Paul Scherrer Institut we integrate data from structural biology, molecular biology, cellular biology and structural bioinformatics to study the molecular basis of GPCR function. Specifically, we aim to obtain the molecular structure of the complexes between GPCRs and their cytoplasmic partners G protein and arrestin, that connect extracellular stimuli to intracellular signals. In addition, we plan to compare the profile of activated signaling molecules with their dynamic intracellular localization pattern to learn how receptor activation translates into specific pathways of cellular signaling. Our goal is to link receptor structure, cellular biological data and pharmacological results to physiological function of GPCRs and thus provides the basis for the development of better drugs.

Direct link to Lay Summary

Last update: 21.02.2013

Active participation

Self-organised

Active participation

Communication	Title	Media	Place	Year

Number	Title	Start	Funding scheme

Class A GPCRs transduce extracellular signals across the cell membrane by activating cytoplasmic-bound heterotrimeric GTP binding proteins (G proteins), which, in turn, modulate the activity of downstream effector proteins. Despite the physiological and pharmacological relevance of GPCRs, the structural basis of ligand efficacy and receptor activation, and how these elements translate into cytoplasmic trafficking and cellular response still remain elusive.In this research project we will integrate the efforts of several research groups from the Laboratory for Biomolecular Research (Biology and Chemistry Department, Paul Scherrer Institut) of different expertise (structural biology, molecular biology, cellular biology and structural bioinformatics), which will focus on specific subprojects (Figure 1, left). First, we will study ligand binding and how it is translated into selectivity and receptor activation, using beta adrenergic receptors as a model system (subproject A). Second, we will obtain the crystal structure of the rhodopsin-transducin complex, which will serve as a general model for the study of GPCR-G protein complexes, the centerpiece that connects extracellular signals to intracellular effectors (subproject B). Third, we will compare the profile of activated signaling molecules with the dynamic intracellular localization pattern to learn how receptor activation translates into specific patterns of cellular signaling. In this case, we will use the serotonin receptor family as a model system, with the specific goal of integrating the analysis of the serotonergic signaling and trafficking map with the biological function of serotonin in the human central nervous system (subproject C). Combination of the data resulting from the study of different Class A GPCRs will allow us to obtain a global picture of GPCR signaling. Our goal is to link receptor structure, cellular biological data and pharmacological results to physiological function. Thus, our project has significant implications in physiology, pharmacology and therapeutics.