![]() Phospholipid liposomes and supported bilayers are other popular membrane mimetics that can harbor membrane proteins in a detergent-free lipid environment, however, they tend to be very non-homogeneous and are not compatible with most of the high resolution structural biology techniques. Detergents can also interfere with the binding of interaction partners as well as with subunit assembly in membrane protein complexes. Even though detergents are easy to handle, they are not ideal for membrane proteins as they may affect sensitive tertiary structure, reduce the MPs' stability and may cause unfolding of the proteins. So far, the most popular membrane mimetics used in membrane protein structural biology are detergent micelles ( Linke, 2009). However, MPs represent a very small fraction of the available protein structures in the Protein Data Bank (PDB), mainly due to challenges in preparing functionally relevant samples in sufficient quantities. Structural information on MPs is a key benefit when seeking new therapeutics, and major efforts have been made toward this aim in the recent years ( Bill et al., 2011 Cheng, 2018). ![]() A majority of approved systemic drugs target membrane proteins due to their involvement in a variety of cellular processes such as signal transduction, transport of ions and molecules across the cell membrane, and cell adhesion to surfaces ( Cournia et al., 2015). Membrane proteins (MPs) play critical roles in health, disease and hence in drug design. In this review, we discuss the recent technical developments in nanodisc technology leading to construction of large nanodiscs and examine some of the implicit applications. Another aspect of exploiting the large available surface area of these novel nanodiscs could be to engineer more realistic membrane mimetic systems with features such as membrane asymmetry and curvature. This enables widening the application of nanodiscs from single membrane proteins to investigating large protein complexes and biological processes such as virus-membrane fusion and synaptic vesicle fusion. Recent advances in nanodisc engineering such as covalently circularized nanodiscs (cND) and DNA corralled nanodiscs (DCND) have opened up the possibility of engineering nanodiscs of size up to 90 nm. Until recently the size of the nanodiscs that could be produced was limited to ~ 16 nm. Phospho-lipid bilayer nanodiscs have gathered much scientific interest as a stable and tunable membrane mimetic for the study of membrane proteins. ![]() 4Renal Division and Engineering in Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.3Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, United States.2Wyss Institute for Biologically Inspired Engineering at Harvard, Boston, MA, United States.1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States.Shih 2,3, Gerhard Wagner 1 and Mahmoud L.
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