Cyclodextrins Self-assembling for cryo-EM structure of flexible Proteins (CORSET)

The project aims to surpass the current state-of-the-art methods in cryo-EM by enabling the determination of complete 3D structures of proteins, including their flexible domains. We propose a novel strategy: encapsulating proteins within cyclodextrin-based supramolecular scaffolds of precisely defined dimensions. This approach will impose constraints on their flexibility, thus limiting the range of conformations they can adopt and facilitating the resolution of their 3D organization.
Our methodology leverages the advanced supramolecular chemistry of cyclodextrin-based assemblies to design functional, dimensionally precise scaffolds. These scaffolds will be modular, adaptable, and capable of selectively binding specific protein domains modified with tags commonly used in biochemistry. In the field of supramolecular chemistry, the proposed self-assembly of functional building blocks is completely original, and the application involving attachment to a protein to constrain its flexibility is unprecedented.
We will develop this strategy to determine the structure of proteins involved in specific region of contact between organelles in eukaryotes. These regions, named membrane contact sites (MCSs), are constituted by protein that bridge apposed organelles and perform major cellular functions, such as lipid transfer, calcium signaling, and organelle dynamics. MCS dysfunction is involved in human diseases, including cancer, obesity, and neurological disorders..

The IPCM (Institut Parisien de Chimie Moléculaire/Parisian Institute for Molecular Chemistry) is a joint research unit between Sorbonne Université and CNRS (Centre National de la Recherche Scientifique).

The expertise in molecular chemistry in the broadest sense, the great diversity of the teams and the laboratory’s high-performance technical platforms lead to research ranging from the structuring of matter on a molecular scale to materials, involving know-how in inorganic and organic chemistry, polymer science, nanoscience, and even the interfaces with biology.
The scientific results of the IPCM, in relation to the major societal challenges, have an impact on fields ranging from health, the environment and new energies to information technologies.

This highly interdisciplinary approach is organized around a collaboration between Matthieu Sollogoub (Sorbonne University, UMR 8232 CNRS), expert in supramolecular and synthetic chemistry and Daniel Lévy with expertise in structural biology and biophysics (Institut Curie UMR 168, CNRS, SU). Both teams have the human resources, expertise, instruments, including a state-of-the-art cryo-electron microscope, and computing power to provide a favorable framework for the realization of a PhD thesis. The candidate must have a strong background in synthetic chemistry and interest in structural biology.