Towards Understanding the Structure and Dynamics of Receptor Proteins

Ziel

Upon binding an agonist, the seven transmembrane (TM) helical bundle of a G-protein coupled receptor (GPCR) undergoes conformational changes that catalyze nucleotide exchange within bound G proteins. In rhodopsin, the agonist arises from light-induced isomerization of the retinal ligand, but an active conformation (Ops*) can also be adopted by the opsin apoprotein. We recently solved the structure of Ops* in complex with a peptide from the C-terminal ±-5 helix of the G protein. Considering this structure and previous work, we postulate a mechanism by which the 40 Å gap between the retinal and the nucleotide binding site is bridged. First, TM5 and TM6 engage in new interactions to form a mitt-like structure into which the G-protein ±-5 helix can bind. Second, the bound ±-5 helix switches into a new position, thereby acting as a transmission rod to the nucleotide binding site. In the proposed project, we will test this mechanism and explore the underlying protein dynamics by: - determining the structure of the receptor in complex with longer peptides, and if possible, with the G holoprotein, - measuring conformational changes on the timescale of receptor activation (ms) and expand computational modelling of the respective transitory complexes, - determining the underlying backbone dynamics and fluctuations on the ps-ns time scale by experimentation and molecular dynamics. Some of the necessary methodologies are available, while others must be developed or made available through collaborations. Rhodopsin is the ideal model system for studying signal transduction mechanisms. Our novel multi-prong approach, while risky, will enormously improve our understanding of GPCR signalling mechanisms. The insights gained will be significant for receptor-directed drug development.

Wissenschaftliches Gebiet

Finanzierungsplan

ERC-AG - ERC Advanced Grant

Gastgebende Einrichtung

CHARITE - UNIVERSITAETSMEDIZIN BERLIN

EU-Beitrag

€ 2 449 840,00

Adresse

Chariteplatz 1
10117 Berlin
Deutschland

Region

Berlin Berlin Berlin

Aktivitätstyp

Higher or Secondary Education Establishments

Hauptforscher

Klaus Peter Hofmann (Prof.)

Kontakt Verwaltung

Martina Eickmann (Ms.)

Links

Die Organisation kontaktieren Website

Gesamtkosten

Keine Daten

Begünstigte (1)