Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine pharmacology and pharmacy drug discovery
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics nucleotides
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
ERC-2009-AdG
See other projects for this call
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Host institution
10117 Berlin
Germany
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.