Objective
Interactions between proteins and small molecules are rich in nature – across organisms, tissues and cellular contexts they underly crucial biological functions in health and disease. One class of small biochemicals, molecular glues (MGs), can selectively induce de novo protein-protein dimerization. Particularly in the context of targeted protein inhibition and degradation, MGs are praised as clinical alternatives to treating diseases driven by proteins that are otherwise pharmacologically intractable. Prominent examples like rapamycin, a MG used in the therapy of kidney tumours, illustrate a key research challenge, however: up until now, most MGs have been discovered by chance. Our limited understanding of their biophysical characteristics prevents us from rationally designing MGs, and from tracing drug resistance mechanisms by target proteins’ mutational escape during cancer evolution.
Here, I propose a scalable experimental strategy to determine the binding profiles of MGs to thousands of target protein mutants in parallel. To perform comparisons of the biophysical impact of mutations on distinct MG mechanisms, I have three major aims: 1.) to develop a deep mutational scanning assay to quantify MG-protein-protein complexation, 2.) to produce the first global atlas of resistance mutations for a classic MG system – rapamycin in complex with MTOR and FKBP12, and 3.) to characterise ABA, a plant hormone which induces heterodimer formation by extensive structural remodelling of only one of its target proteins.
“DeepGlue” will take place under the experienced supervision of Prof. Ben Lehner (CRG Barcelona), whose group has pioneered the use of deep mutagenesis to understand protein structures, dynamics and interactions. Within this environment, my action will be uniquely positioned to transcend the dynamic fields of Chemical Biology, Protein Biophysics and Cancer Evolution – aspiring to deliver fundamental insights that ultimately shape new and better therapies.
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.
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences biophysics
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
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.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
MAIN PROGRAMME
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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.
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.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) HORIZON-MSCA-2022-PF-01
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
08003 Barcelona
Spain
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.