Abstract
Membrane proteins work within asymmetric bilayers of lipid molecules that are critical for their biological structures, dynamics and interactions. These properties are lost when detergents dislodge lipids, ligands and subunits, but are maintained in native nanodiscs formed using styrene maleic acid (SMA) and diisobutylene maleic acid (DIBMA) copolymers. These amphipathic polymers allow extraction of multicomponent complexes of post-translationally modified membrane-bound proteins directly from organ homogenates or membranes from diverse types of cells and organelles. Here, we review the structures and mechanisms of transmembrane targets and their interactions with lipids including phosphoinositides (PIs), as resolved using nanodisc systems and methods including cryo-electron microscopy (cryo-EM) and X-ray diffraction (XRD). We focus on therapeutic targets including several G protein-coupled receptors (GPCRs), as well as ion channels and transporters that are driving the development of next-generation native nanodiscs. The design of new synthetic polymers and complementary biophysical tools bodes well for the future of drug discovery and structural biology of native membrane:protein assemblies (memteins).
Highlights
Obtaining accurate kinetic and structural information about molecular interactions of biologically relevant states of therapeutic targets is the foundation of modern drug discovery
A significant body of evidence of how native nanodiscs can be produced by a family of styrene maleic acid (SMA)-related polymers has emerged over the past decade
The range of polymer types is allowing structure–activity relationships to emerge, informing the development of new polymers that are zwitterionic, tagged, more homogeneous, conformationally restrained and/or circularized for giving optimal performance for demanding transmembrane targets. Such tools are allowing the preparation of endogenous complexes that are unsuitable for detergent extraction or reassembly for structure–function analysis and high-throughput screening
Summary
Obtaining accurate kinetic and structural information about molecular interactions of biologically relevant states of therapeutic targets is the foundation of modern drug discovery This endeavour is complicated by the fact that most targets are embedded in asymmetric lipid bilayers with signaling lipids, post-translational modifications, cofactors and heteromeric subunits. Targeting native states while keeping the original lipids, cofactors, modifications and partner proteins bound is clearly critical for discovery of drug molecules with higher selectivity and fewer side effects. This effort has led to the development of a growing set of synthetic SMA-derived copolymers including SMA and its derivatives (Figure 1) that convert membranes from cells or tissues into native nanodiscs containing membrane:protein assemblies (memteins) for high-throughput screening and structure determination. Seminal studies highlighting the potential to characterize native-state complexes
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