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Zooming in on small-molecule ligands by magnetic resonance

Objective

Small molecules are critical players in the chemistry of life. In the role of substrates, cofactors, solvent, inhibitors or activators, they steer the activities of proteins and nucleic acids. For mechanistic studies, it would be desirable to single out a small ligand from a large macromolecular complex, even if their sizes lie several orders of magnitude apart, and follow its fate during chemical and structural transformations. Few experimental techniques would achieve this under native conditions.
NMR spectroscopy grants insights into molecular motions, interactions and chemical transitions at atomic-level resolution. However, it faces challenges when observing small-molecule ligands within large complexes: The first prerequisite are NMR active nuclei. Unlike biomolecular NMR, where isotope labelling is routine, the site-directed introduction of desired nuclei into small molecules still requires lengthy, individual synthesis. Second, transverse-relaxation optimised experiments have been instrumental in pushing the size limits of protein-observed NMR into the biologically relevant range of tens to hundreds of kilodaltons. Such experiments are not directly transferable to the small molecule space due to its different chemical build-up.
ZoomNMR proposes to cover this blind spot with a spectroscopic toolbox for ligand-detected NMR of large macromolecular complexes. Our approach capitalizes on late-stage isotope labelling strategies, inspired by organic chemistry, in conjunction with relaxation interference phenomena to maximize sensitivity and resolution. The tools will be implemented on a prototypical human enzyme and three exemplary ligand classes. We will deliver a proof-of-concept that our novel methodology can tackle diverse research problems, from fundamental mechanistic enzymology to the design of drug molecules. Our future vision is that ligand-observed NMR of large complexes will become as straightforward and efficient as protein-observed NMR is today.

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Topic(s)

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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2024-COG

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Host institution

LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Net EU contribution

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.

€ 1 999 969,00
Address
GESCHWISTER SCHOLL PLATZ 1
80539 MUNCHEN
Germany

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Region
Bayern Oberbayern München, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
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Total cost

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.

€ 1 999 969,00

Beneficiaries (1)

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