The usage of the lipid bilayer nanodiscs (ND) system for Nuclear Magnetic Resonance (NMR)-based studies has led to both enthusiasm and frustration in many labs in the recent years.

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| The choice of a suitable membrane mimicking environment is of fundamental importance for the characterization of structure and function of membrane proteins. In this respect, usage of the lipid bilayer nanodisc technology provides a unique potential for NMR-based studies.

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In general, structural studies can be strongly dependent on the target protein's environment. As such, the influence of the environment on the protein structure as well as on the used experimental technique has to be considered. This is particularly true for the NMR-based investigation of membrane proteins (MPs), which require a suitable membrane mimicking environment to promote a protein conformation that is, on the one hand, representative for its native behavior and, on the other, compatible with the requirements of NMR spectroscopy. While a variety of different membrane mimetics for solution and/or solid-state NMR have been established, the lipid bilayer nanodisc system distinctively combines various potentially advantageous properties including:

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• a native-like lipid surrounding, the absence of detergents,

• sample homogeneity,

• isolation of defined oligomeric states,

• and good accessibility of extra membranous domains.

Noteworthy, these properties also make the ND system attractive as a tool for structural studies for non-NMR techniques such as, for instance, cryo EM or X-ray crystallography studies of membrane proteins.

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Working with nanodiscs

The usage of the nanodiscs system requires a number of steps that should be carefully considered to obtain optimal NMR insights into the desired target protein.