Project description
Improving how we observe large biomolecular assemblies with nuclear magnetic resonance spectroscopy
Despite advances in nuclear magnetic resonance (NMR), the study of large biomolecular assemblies is limited by signal overlaps, poor sensitivity and line broadening. To address this, the ERC-funded XXL-NMR project aims to develop methods that will simplify NMR spectra and related site-specific analysis. First, it will design a site-specific labelling method to enable the observation of NMR signals for targeted sites in large proteins. It will also create a combinatorial strategy to reduce the time needed for site-specific identification of individual NMR signals. New NMR experiments will be developed to improve both the resolution and sensitivity of NMR spectra of very large complexes. Finally, it will demonstrate these novel NMR methods on large biological complexes such as therapeutic antibodies and ribosomes.
Objective
The cell is a collection of dynamic molecular machines. NMR spectroscopy is the method of choice to observe, at atomic resolution, complex conformational changes, transient interactions and dynamics of proteins. Introduction of methyl specific labelling technology has enabled solution NMR studies of protein assemblies of several hundred kDa. However, this strategy is mostly restricted to symmetrical and thermostable protein assemblies, precluding applications to large medically relevant biological complexes. The increases of linewidths and the high number of signal overlaps hamper the NMR spectra analysis of most hetero-oligomeric large assemblies studied at room temperature. In this project, we will develop two complementary concepts to significantly simplify both NMR spectra and corresponding site specific analysis. We will build a multi-site specific labelling method enabling observation of NMR signals only for the sites of interest in a large protein complex. We will invent a combinatorial strategy to reduce the time required for site-specific identification of each individual NMR signal from a few months to a few hours. New 1H-frequencies edition schemes will be introduced to enhance significantly the NMR spectras resolution of very slow tumbling biological particles. These groundbreaking NMR methods will be validated using therapeutic antibodies (150 kDa), ribosome (2.4 MDa) samples, and will be used directly to capture the mechanisms of ATP-fueled human chaperonin (1 MDa) in complex with the aggregation prone form of Huntingtin. This project will provide new technological breakthroughs to push biological applications of NMR significantly beyond its current boundaries. We anticipate that the simplification of the NMR analysis resulting from the new developed NMR routes will transform the solution NMR spectroscopy in a very competitive method to study large medically relevant biomolecular assemblies and molecular machines, so far considered as untargetable.
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 physical sciences optics spectroscopy
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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.1.1 - European Research Council (ERC)
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Topic(s)
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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
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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-ERC - HORIZON ERC Grants
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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.
(opens in new window) ERC-2022-ADG
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75794 PARIS
France
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