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Structural basis of G protein-coupled receptor activation by biased ligands

English title Structural basis of G protein-coupled receptor activation by biased ligands
Applicant Deupi Xavier
Number 146520
Funding scheme Project funding (Div. I-III)
Research institution Condensed Matter Theory Paul Scherrer Institut
Institution of higher education Paul Scherrer Institute - PSI
Main discipline Biophysics
Start/End 01.04.2013 - 31.03.2016
Approved amount 288'550.00
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All Disciplines (2)

Discipline
Biophysics
Molecular Biology

Keywords (5)

biased signaling; GPCRs; beta adrenergic receptors; molecular dynamics simulations; angiotensin receptors

Lay Summary (German)

Lead
Eine Reihe synthetisch hergestellter Moleküle versprechen die Nebenwirkungen etablierter Medikamente zu reduzieren. Diese als parteiische Liganden (biased Ligands) bezeichneten Moleküle binden bevorzugt nur eine bestimmte Form von zellulären Rezeptoren und rufen daher auch nur eine bestimmte Reaktion hervor. In diesem Projekt untersuchen wir wo und wie diese Moleküle an ihren jeweiligen Rezeptor binden.
Lay summary

Inhalt und Ziel des Forschungsprojekts
Unsere Forschung zielt dabei auf eine Klasse von zellulären Rezeptoren mit besonderer Bedeutung für die menschliche Physiologie, da sie die Kommunikation zwischen Zellen vermitteln und daher auch prinzipiell in jeder Zelle unseres Körpers vorkommen. Die Kommunikation findet dabei über die G Protein genannte Klasse von Proteinen statt, weswegen die Rezeptoren als G Protein-gekoppelte Rezeptoren (GPCRs) bezeichnet werden. Fehlfunktionen in GPCRs sind eine häufige Ursache von Krankheiten. Auf der anderen Seite zielen 30% aller heutigen Medikamente auf eine Optimierung der GPCR Aktivität um Krankheiten zu lindern oder zu heilen.  
Trotz der enormen Bedeutung von GPCRs, verstehen wir noch zu wenig über wie genau Medikamente mir ihrem jeweiligen Rezeptor interagieren. Vor allem verstehen wir nicht wie parteiische Liganden zielgerichtet nur spezielle Reaktionen in der Zelle hervorrufen. In diesem Projekt untersuchen wir diese Frage mittels einer Kombination von biochemischer Analyse, Röntgenkristallographie und computergestützten Simulationen. 

Wissenschaftlicher und gesellschaftlicher Kontext
Die Ergebnisse dieser Arbeit werden dazu beitragen die Interaktionen zwischen Medikamenten und zellulären Rezeptoren auf der molekularen Ebene zu verstehen und sind daher von Bedeutung für die Entwicklung einer neuen Generation von zielgerichteten Medikamenten in der pharmazeutischen Industrie.

Direct link to Lay Summary Last update: 27.02.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor.
Isogai Shin, Deupi Xavier, Opitz Christian, Heydenreich Franziska M, Tsai Ching-Ju, Brueckner Florian, Schertler Gebhard F X, Veprintsev Dmitry B, Grzesiek Stephan (2016), Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor., in Nature, 530(7589), 237-241.
Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region.
Venkatakrishnan A J, Deupi Xavier, Lebon Guillaume, Heydenreich Franziska M, Flock Tilman, Miljus Tamara, Balaji Santhanam, Bouvier Michel, Veprintsev Dmitry B, Tate Christopher, Schertler Gebhard F X, Babu M Madan (2016), Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region., in Nature, 536(7617), 484-487.
Conformational activation of visual rhodopsin in native disc membranes.
Malmerberg Erik, M Bovee-Geurts Petra H, Katona Gergely, Deupi Xavier, Arnlund David, Wickstrand Cecilia, Johansson Linda C, Westenhoff Sebastian, Nazarenko Elena, Schertler Gebhard F X, Menzel Andreas, de Grip Willem J, Neutze Richard (2015), Conformational activation of visual rhodopsin in native disc membranes., in Science Signaling, 8(367), ra26.
Probing Gαi1 protein activation at single-amino acid resolution.
Sun Dawei, Flock Tilman, Deupi Xavier, Maeda Shoji, Matkovic Milos, Mendieta Sandro, Mayer Daniel, Dawson Roger J P, Schertler Gebhard F X, Babu M Madan, Veprintsev Dmitry B (2015), Probing Gαi1 protein activation at single-amino acid resolution., in Nature Structural & Molecular Biology, 22(9), 686-694.
Functional map of arrestin-1 at single amino acid resolution.
Ostermaier Martin K, Peterhans Christian, Jaussi Rolf, Deupi Xavier, Standfuss Jörg (2014), Functional map of arrestin-1 at single amino acid resolution., in PNAS, 111(5), 1825-1830.
Structural and functional characterization of alternative transmembrane domain conformations in VEGF receptor 2 activation.
Manni Sandro, Mineev Konstantin S, Usmanova Dinara, Lyukmanova Ekaterina N, Shulepko Mikhail A, Kirpichnikov Mikhail P, Winter Jonas, Matkovic Milos, Deupi Xavier, Arseniev Alexander S, Ballmer-Hofer K (2014), Structural and functional characterization of alternative transmembrane domain conformations in VEGF receptor 2 activation., in Structure/Folding and Design, 22(8), 1077-1089.

Collaboration

Group / person Country
Types of collaboration
Jean Peters (Biozentrum, University of Basel) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
MRC Laboratory of Molecular Biology Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Biochemistry and Immunology, Faculty of Medicine of Ribeirão Preto, University of São Paulo Brazil (South America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Laboratory of Biomolecular Research. Biology and Chemistry department. Paul Scherrer Institut Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
D-BIOL-Symposium 2016 (conference organized by the Department of Biology of ETH Zurich) Poster Molecular Basis of Biased Signaling in the angiotensin II type 1 receptor 13.02.2017 Davos, Switzerland Matkovic Milos;
GLISTEN conference (joint meeting between the COST-funded program GLISTEN (CM1207) and the DFG-funded Research Training Group “Medicinal Chemistry of Selective GPCR Ligands” (GRK 1910). Talk given at a conference Backbone NMR spectroscopy reveals allosteric activation networks in the β1 adrenergic receptor 06.04.2016 Erlangen, Germany Deupi Xavier;
In Silico tools in drug design and target discovery Talk given at a conference Detection of ligand-induced conformational changes in GPCR activation by NMR 29.02.2016 Barcelona, Spain Deupi Xavier;
GPCR Workshop 2015 Talk given at a conference Backbone NMR reveals allosteric signaling networks in the beta 1 adrenergic receptor 01.12.2015 Kona, United States of America Deupi Xavier;
19th STS Meeting "Signal Transduction - Receptors, Mediators and Genes" Talk given at a conference A revolution in GPCR structural biology: who, what, when, and why. 02.11.2015 Weimar, Germany Deupi Xavier;
IV New trends in Computational Chemistry for Industry Applications Talk given at a conference Structural and dynamic basis of G protein-coupled receptor activation 01.10.2015 Barcelona, Spain Deupi Xavier;
Kinin 2015 Brazil - International Meeting on Kinin System and Peptide Receptors Talk given at a conference Structural insights into agonist-induced activation of G protein-coupled receptors 21.07.2015 Sao Paulo, Brazil Deupi Xavier;
Retreat of the Ph.D. Program in Biomolecular Structure and Mechanism (ETHZ, University of Zurich) Talk given at a conference Molecular basis of biased signaling in the angiotensin II type 1 receptor 11.06.2015 Liestal, Switzerland Matkovic Milos;
Annual meeting of the German Society of Pharmacology (DGPT) Talk given at a conference Molecular pharmacology of G protein-coupled receptors 12.03.2015 Kiel, Germany Deupi Xavier;
46th Brazilian Congress of Pharmacology and Experimental Therapeutics Talk given at a conference Structural basis of GPCR activation 21.10.2014 Fortaleza, Brazil Deupi Xavier;
Exploring the Biology of GPCRs from in vitro to in vivo Talk given at a conference From structure to dynamics 25.08.2014 Leiden, Netherlands Deupi Xavier;
D-BIOL-Symposium 2014 (conference organized by the Department of Biology of ETH Zurich) Poster Structural Studies of the Angiotensin II Type 1 Receptor: Towards Crystallographic Investigations of Structure and Activation Mechanisms 10.06.2014 Davos, Switzerland Deupi Xavier; Piscitelli Chayne;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved


Associated projects

Number Title Start Funding scheme
135754 Structural characterisation of ligand-induced conformational changes in G protein coupled receptors 01.05.2011 Project funding (Div. I-III)
192780 Structural determinants of recognition and selectivity in GPCR-G protein complexes 01.04.2020 Project funding (Div. I-III)

Abstract

G protein-coupled receptors (GPCRs) are a large family of membrane proteins that transmit the information carried by extracellular signals (like natural ligands or therapeutic drugs) into the cell by activating G protein- or arrestin-mediated intracellular signaling pathways. GPCRs are key in cell physiology and constitute one of the most important pharmaceutical targets. Despite their significance, we are just starting to understand the molecular mechanisms by which ligands modulate GPCR activity. For instance, in recent years many researchers have shown that G protein- and arrestin-mediated signaling pathways can be modulated with “biased ligands”. The concept of “biased agonism” has become an important concept of clinical relevance in modern pharmacology, as ligands with biased properties hold promise to become better drugs, with fewer side effects caused by promiscuous activation of cellular signaling pathways. However, design of such biased agonists requires a better understanding at a molecular level on how ligands activate GPCRs. There is ample evidence that GPCRs adopt multiple conformations along their activation pathway. Biased ligands would preferentially stabilize some of these conformations, which would result in a better interaction with a specific intracellular partner, resulting in the preferred activation of a particular signaling pathway.This project aims to gain a better understanding of how biased ligands activate GPCRs. We will focus on the beta adrenergic and angiotensin receptors, where biased signaling is best described. We will combine experimental data from X-ray crystallography and biophysical studies (phi-value analysis and fluorescence spectroscopy) with state-of-the-art (adiabatic biased and well-tempered metadynamics) molecular dynamics simulations to obtain structural information of intermediate active states and to calculate the energy landscapes associated to receptor activation by biased ligands.Our results will allow a more detailed understanding of how biased ligands stabilize specific GPCR active conformations. We expect that this knowledge will facilitate the development of improved therapeutic agents that target GPCRs with improved efficacy and fewer side effects.
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