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Linking G protein-coupled receptor structure to signaling output

English title Linking G protein-coupled receptor structure to signaling output
Applicant Schertler Gebhard
Number 132815
Funding scheme Project funding
Research institution GPCR Signalling Biomolecular Research Paul Scherrer Institute
Institution of higher education Paul Scherrer Institute - PSI
Main discipline Molecular Biology
Start/End 01.12.2010 - 30.11.2013
Approved amount 600'000.00
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All Disciplines (4)

Discipline
Molecular Biology
Biophysics
Biochemistry
Cellular Biology, Cytology

Keywords (7)

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

Lay Summary (English)

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

Responsible applicant and co-applicants

Employees

Publications

Publication
AAscan, PCRdesign and MutantChecker: A Suite of Programs for Primer Design and Sequence Analysis for High-Throughput Scanning Mutagenesis
Sun Dawei, Ostermaier Martin K., Heydenreich Franziska M., Mayer Daniel, Jaussi Rolf, Standfuss Joerg, Veprintsev Dmitry B. (2013), AAscan, PCRdesign and MutantChecker: A Suite of Programs for Primer Design and Sequence Analysis for High-Throughput Scanning Mutagenesis, in PLOS ONE, 8(10), e78878.
Constitutively active rhodopsin mutants causing night blindness are effectively phosphorylated by GRKs but differ in arrestin-1 binding
Vishnivetskiy Sergey. A., Ostermaier Martin K., Singhal Ankita, Panneels Valerie, Homan Kristoff T., Glukhova Alisa, Sligar Stephen G., Tesmer John J. G., Schertler Gebhard F. X., Standfuss Joerg, Gurevich Vsevolod V. (2013), Constitutively active rhodopsin mutants causing night blindness are effectively phosphorylated by GRKs but differ in arrestin-1 binding, in CELLULAR SIGNALLING, 25(11), 2155-2162.
Insights into congenital stationary night blindness based on the structure of G90D rhodopsin
Singhal Ankita, Ostermaier Martin K., Vishnivetskiy Sergey A., Panneels Valerie, Homan Kristoff T., Tesmer John J. G., Veprintsev Dmitry, Deupi Xavier, Gurevich Vsevolod V., Schertler Gebhard F. X., Standfuss Joerg (2013), Insights into congenital stationary night blindness based on the structure of G90D rhodopsin, in EMBO REPORTS, 14(6), 520-526.
Molecular signatures of G-protein-coupled receptors
Venkatakrishnan Anna J., Deupí Xavier, Lebon Guillaume, Tate Christopher G., Schertler Gebhard FX X, Madan Babu M. (2013), Molecular signatures of G-protein-coupled receptors, in Nature, 494(7436), 185-194.
Practical aspects in expression and purification of membrane proteins for structural analysis.
Vinothkumar Kutti R, Edwards Patricia C, Standfuss Joerg (2013), Practical aspects in expression and purification of membrane proteins for structural analysis., in Schmidt-Krey Ingeborg (ed.), Humana Press (Springer), NY USA, 17-30.
Production of GPCR and GPCR complexes for structure determination
Maeda Shoji, Schertler Gebhard FX X (2013), Production of GPCR and GPCR complexes for structure determination, in Current Opinion in Structural Biology, 23(3), 381-392.
Relation between sequence and structure in membrane proteins
Olivella Mireia, Gonzalez Angel, Pardo Leonardo, Deupí Xavier (2013), Relation between sequence and structure in membrane proteins, in Bioinformatics, 29(13), 1589-1592.
Relevance of rhodopsin studies for GPCR activation
Deupí Xavier (2013), Relevance of rhodopsin studies for GPCR activation, in Biochimica et Biophysica Acta - Bioenergetics, 1.
Structure of β-adrenergic receptors
Brueckner Florian, Piscitelli Chayne L., Tsai Chingju, Standfuss Jörg, Deupí Xavier, Schertler Gebhard FX X (2013), Structure of β-adrenergic receptors, in Methods in Enzymology, 520, 117-151.
Two alternative conformations of a voltage-gated sodium channel
Tsai Chingju, Tani Kazutoshi, Irie Katsumasa, Hiroaki Yoko, Shimomura Takushi, McMillan Duncan G G, Cook Gregory M., Schertler Gebhard FX X, Fujiyoshi Yoshinori, Li Xiaodan (2013), Two alternative conformations of a voltage-gated sodium channel, in Journal of Molecular Biology, 425(22), 4074-4088.
Conserved activation pathways in G-protein-coupled receptors
Deupi X, Standfuss J, Schertler G (2012), Conserved activation pathways in G-protein-coupled receptors, in BIOCHEMICAL SOCIETY TRANSACTIONS, 40, 383-388.
Ligands Stabilize Specific GPCR Conformations: But How?
Deupi X, Li XD, Schertler GFX (2012), Ligands Stabilize Specific GPCR Conformations: But How?, in STRUCTURE, 20(8), 1289-1290.
Quantification of structural distortions in the transmembrane helices of GPCRs.
Deupi Xavier (2012), Quantification of structural distortions in the transmembrane helices of GPCRs., in Vaidehi Nagarajan (ed.), Humana Press (Springer), NY USA, 219-35.
Stabilized G protein binding site in the structure of constitutively active metarhodopsin-II.
Deupi Xavier, Edwards Patricia, Singhal Ankita, Nickle Benjamin, Oprian Daniel, Schertler Gebhard, Standfuss Jörg (2012), Stabilized G protein binding site in the structure of constitutively active metarhodopsin-II., in Proceedings of the National Academy of Sciences of the United States of America, 109(1), 119-24.
Membranes.
Stroud Robert M, Schertler Gerhard F X (2011), Membranes., in Current opinion in structural biology, 21(4), 495-6.
Molecular Basis of Ligand Dissociation in beta-Adrenergic Receptors
Gonzalez A, Perez-Acle T, Pardo L, Deupi X (2011), Molecular Basis of Ligand Dissociation in beta-Adrenergic Receptors, in PLOS ONE, 6(9), e23815.
Preparation of an activated rhodopsin/transducin complex using a constitutively active mutant of rhodopsin.
Xie Guifu, D'Antona Aaron M, Edwards Patricia C, Fransen Maikel, Standfuss Jorg, Schertler Gebhard F X, Oprian Daniel D (2011), Preparation of an activated rhodopsin/transducin complex using a constitutively active mutant of rhodopsin., in Biochemistry, 50(47), 10399-407.
Structural insights into agonist-induced activation of G-protein-coupled receptors.
Deupi Xavier, Standfuss Jörg (2011), Structural insights into agonist-induced activation of G-protein-coupled receptors., in Current opinion in structural biology, 21(4), 541-51.
Functional map of arrestin-1 at single amino acid resolution
Ostermaier Mart, Peterhans Christian, Jaussi Rolf, Deupi Xavier, Standfuss Jörg, Functional map of arrestin-1 at single amino acid resolution, in PNAS.

Collaboration

Group / person Country
Types of collaboration
Actelion Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
- Industry/business/other use-inspired collaboration
Vanderbilt University, Gurevich group United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
GPCR Workshop Poster Insights into congenital stationary night blindness based on the structures of constitutively active rhodopsins 01.12.2013 Maui, United States of America Deupi Xavier; Singhal Ankita;
Royal Society bioXFEL Conf Individual talk Session Chair 14.10.2013 London, Great Britain and Northern Ireland Schertler Gebhard;
ESRF User Meeting Talk given at a conference Structures determination of G-protein coupled receptors using microfocus beamlines 05.02.2013 Grenoble, France Schertler Gebhard;
Nagoya Symposium: Frontiers in Structural Physiology Talk given at a conference Structures of G-protein coupled receptors with agonists and antagonists relevant to pharmacologie and disease 25.01.2013 Nagoya, Japan Schertler Gebhard;
5th Würzburg GPCR Symposium Talk given at a conference Structure of G protein-coupled receptors 16.10.2012 Würzburg, Germany, Germany Schertler Gebhard;
15th International Conference on Retinal Proteins Talk given at a conference The structural basis of congential stationary night blindness 30.09.2012 Ascona, Switzerland, Switzerland Standfuss Joerg; Ostermaier Martin; Singhal Ankita; Deupi Xavier; Schertler Gebhard;
4th RSC/SCI Symposium on GPCRs Medicinal Chemistry Talk given at a conference Structure of G protein-coupled receptors 18.09.2012 Lilly, United Kingdom, Great Britain and Northern Ireland Schertler Gebhard;
Italian Crystallography Symposium Talk given at a conference Structure of G protein-coupled receptors 10.09.2012 Verona, Italy, Italy Schertler Gebhard;
XXIInd EFMC International Symposium on Medicinal Chemistry Talk given at a conference Structures of Active and Inactive G Protein Coupled Receptors: Implications for the Activation Mechanism and Pharmacology 05.09.2012 Berlin, Germany Schertler Gebhard;
EFMC-ISMC Berlin Talk given at a conference Structure of G protein-coupled receptors 03.09.2012 Berlin, Germany, Germany Schertler Gebhard;
NCCR MUST Symposium Talk given at a conference Tutorial: Ultrafast Biology 22.06.2012 ETHZ Hönggerberg, Switzerland Schertler Gebhard;
NCC2012 conference Talk given at a conference Structure of G protein-coupled receptors 14.05.2012 Amsterdam, Netherlands, Switzerland Schertler Gebhard;
Vortrag Berner Chemische Gesellschaft Individual talk Structures of Active and Inactive G Protein Coupled Receptors: Implications for the Activation Mechanism and Pharmacology 09.05.2012 Bern, Switzerland Schertler Gebhard;


Self-organised

Title Date Place
15th International Conference on Retinal Proteins 30.09.2012 Ascona, Switzerland, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media A glimpse inside the control centres of cell communication press release International 2013
Media relations: print media, online media How botox binds to neurons German-speaking Switzerland Western Switzerland 2013
Media relations: radio, television «Und der Nobelpreis ging an ...»: Was genau leisteten die ausgezeichneten Chemiker? DRS2 German-speaking Switzerland 2012
Media relations: print media, online media Nobelpreiswürdig: G-Protein-gekoppelte Rezeptoren Press Release International German-speaking Switzerland Western Switzerland 2012
Media relations: print media, online media The basic structures of sight deciphered Press Release International German-speaking Switzerland Western Switzerland 2011
Media relations: print media, online media Wenn die Datenleitung in der Zelle versagt Western Switzerland German-speaking Switzerland 2011

Associated projects

Number Title Start Funding scheme
153145 Serial femtosecond crystallography of GPCR signaling systems 01.06.2014 Project funding
135754 Structural characterisation of ligand-induced conformational changes in G protein coupled receptors 01.05.2011 Project funding
192780 Structural determinants of recognition and selectivity in GPCR-G protein complexes 01.04.2020 Project funding
133810 Upgrading the biophysical facility at PSI with analytical ultracentrifuge equipped with fluorescence detection system. 01.12.2010 R'EQUIP
141235 Structural impact of pathological mutations on the GPCR rhodopsin and its complex with arrestin 01.05.2012 Project funding
153145 Serial femtosecond crystallography of GPCR signaling systems 01.06.2014 Project funding
146975 Trafficking and Signaling of Disease-Related Receptor Complexes 01.04.2014 Project funding
141898 NMR studies of GPCRs: Structure, dynamics and interactions with ligands and signaling proteins 01.12.2012 Sinergia

Abstract

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.
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