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Structural determinants of recognition and selectivity in GPCR-G protein complexes

English title Structural determinants of recognition and selectivity in GPCR-G protein complexes
Applicant Deupi Xavier
Number 192780
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 01.04.2020 - 31.03.2024
Approved amount 588'204.00
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All Disciplines (2)

Discipline
Biophysics
Molecular Biology

Keywords (5)

G protein signaling; Structural bioinformatics; Structural biology; G proteins; G protein coupled receptors

Lay Summary (German)

Lead
Dynamische Proteinkomplexe an der Zelloberfläche leiten Informationen in die Zelle weiter. In diesem Projekt wollen wir einen besseren Einblick in einen Schlüsselaspekt der Zellphysiologie erlangen indem wir die Struktur und Dynamik dieser Komplexe untersuchen um zu verstehen wie deren Bildung spezifische Signalwege auslöst.
Lay summary
Ziele des Forschungsprojekts

Die Kommunikation mit der Umwelt ist für alle Lebewesen von zentraler Bedeutung. Auf zellulärer Ebene wird diese oft von Proteinen vermittelt, die in die Zellmembran eingebettet sind und sowohl in Kontakt mit der Umgebung als auch mit dem Zellinneren stehen sind und als "zelluläre Gegensprechanlagen" fungieren. G-Protein-gekoppelte Rezeptoren (GPCRs) sind aufgrund ihrer Diversität und Prävalenz eine der wichtigsten Gruppen solcher Rezeptoren. Bei Ihnen führt die Bindung von äusseren (extrazellulären) sogenannte Liganden (wie Geruchsstoffen, Hormonen und therapeutischen Arzneimitteln) zur Rekrutierung und Aktivierung von inneren (intrazellulären) G-Proteinen. Dies führt dazu, das die im Liganden codierte Information in intrazelluläre Protein-Protein-Wechselwirkungen “ übersetzt” wird, was zu einer Signalantwort der Zelle führen. Wir verstehen erst ansatzweise  wie GPCRs und G-Proteine interagieren, um diese komplexen Signalantworten zu erzeugen, die mit der selektiven Bildung eines Komplexes zwischen dem aktiven Rezeptor und einem bestimmten G-Protein-Subtyp beginnen.
In diesem Projekt werden wir strukturelle und dynamische Daten bestehender GPCR / G-Proteinkomplexe mithilfe von Bioinformatik-Tools analysieren. Dies wird neue Modelle für die Rekrutierung und Selektivität von GPCR-G-Proteinen generieren, die in meiner Gruppe verwendet werden, um weitere Experimente zu entwerfen und neue Daten zu interpretieren, die von unseren nationalen und internationalen Partnern zur Verfügung gestellt werden.

Wissenschaftlicher und gesellschaftlicher Kontext

GPCRs sind für die medizinische Forschung außerordentlich wichtig, da ihre Fehlfunktion häufig zu Krankheiten führt. Etwa 30% aller auf dem Markt befindlichen Arzneimittel wirken über diese Rezeptoren. Unsere Ergebnisse werden neue Einblicke in die molekulare Basis von GPRC / G-Protein-Wechselwirkungen GPCR-vermittelte Signalübertragung liefern.
Direct link to Lay Summary Last update: 06.04.2020

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
132815 Linking G protein-coupled receptor structure to signaling output 01.12.2010 Project funding (Div. I-III)
183563 PrP and its receptor GPR126: guardians of axomyelinic integrity and druggable targets against demyelinating diseases 01.02.2019 Sinergia
160805 Targeting Cancer Cells with Hybrid and Heterovalent Ligands at Controlled Distances 01.02.2016 Sinergia
146520 Structural basis of G protein-coupled receptor activation by biased ligands 01.04.2013 Project funding (Div. I-III)

Abstract

Communication with the environment is a key aspect of life. At the cellular level, this task can be carried out by proteins embedded in the cell membrane, which are exposed both to the extracellular environment and to the cytoplasm, and can thus act as 'cellular intercoms'. Due to their diversity and prevalence, G protein-coupled receptors (GPCRs) are one of the most important groups of such signaling membrane receptors. In essence, binding of extracellular ligands to GPCRs results in the recruitment and activation of intracellular G proteins. This mechanism allows to translate the information encoded in endogenous ligands or pharmaceutical drugs into a complex set of intracellular protein-protein interactions that ultimately result in a concerted cellular signaling response (e.g. release of secondary messengers or activation of enzymes). We are just beginning to understand how GPCRs and their intracellular effectors interact to generate these complex signaling cascades, which begin with the selective formation of a complex between the active receptor and a specific G protein subtype.The recent analysis of two 3D structures of such complexes (in collaboration with colleagues at the Paul Scherrer Institute) has led to the identification of two new domains of the receptor possibly involved in G protein recognition and selectivity: the fourth intracellular loop (ICL4) and the proximal part of the C-terminus. Remarkably, one of these structures revealed an unexpected interaction of the receptor C-terminus with the Gß? subunit of the G protein, leading to new hypotheses on the role of these domains in GPCR signaling. In this project, I plan to leverage my experience in structural bioinformatics to analyze the role of these domains in GPCR/G protein recognition. To do so, I plan to design and build a set of bioinformatics tools for large-scale analysis of specific domains in GPCRs and G proteins. These tools will provide a large and rich set of data on structure, function, and phylogeny that will allow in-depth statistical analysis of the role of certain regions (such as ICL4) in selective GPCR/G protein recognition. This ‘structural analysis platform’ will set the basis for future studies in my group and, ideally, by researchers worldwide. I plan to complement this work by using molecular simulations (flexible protein-protein docking and replica-exchange molecular dynamics simulations) of GPCR-G protein complexes to gain a better understanding of the dynamic role of the C-terminus of GPCRs in G protein recruitment. Specifically, analysis of the trajectories will allow us to evaluate the ability of the C-terminus to maintain a stable interaction with the Gß? subunit, how this affect the mobility of the Ga subunit, and what is the effect of lipid modifications in the receptor and the G protein. Our findings will provide new data on the role of each of these elements in stabilizing the complexes and, ultimately, in the molecular basis of signaling. This work will generate new theoretical models of GPCR-G protein recruitment and selectivity that will be used in my group to design new experiments and to interpret new data obtained by our collaborators in Switzerland and worldwide.GPCRs are extraordinarily important in human physiology, as their malfunction often results in disease. They also constitute one of the most important pharmaceutical targets, with around 30% of the drugs acting through these receptors. However, we are just beginning to understand the interplay between their structure, their dynamic behavior, and their signaling properties. Our results will provide new insights in the field of GPCR-mediated signaling that could later be used to develop safer and more effective new pharmaceutical drugs.
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