Lipid nanoparticle technologies for the study of G protein-coupled receptors in lipid environments

Abstract

G protein-coupled receptors (GPCRs) are a large family of integral membrane proteins which conduct a wide range of biological roles and represent significant drug targets. Most biophysical and structural studies of GPCRs have been conducted on detergent-solubilised receptors, and it is clear that detergents can have detrimental effects on GPCR function. Simultaneously, there is increasing appreciation of roles for specific lipids in modulation of GPCR function. Lipid nanoparticles such as nanodiscs and styrene maleic acid lipid particles (SMALPs) offer opportunities to study integral membrane proteins in lipid environments, in a form that is soluble and amenable to structural and biophysical experiments. Here, we review the application of lipid nanoparticle technologies to the study of GPCRs, assessing the relative merits and limitations of each system. We highlight how these technologies can provide superior platforms to detergents for structural and biophysical studies of GPCRs and inform on roles for protein-lipid interactions in GPCR function.

Keywords: G protein-coupled receptor; Lipid-protein interactions; Lipodisq; Nanodisc; SMALP; rHDL.

Fig. 1

A GPCR lipid nanoparticle. Lipid nanoparticles consist of phospholipids in a discoidal bilayer, solubilised by an amphipathic polymer or protein. Both the ligand-binding face and G protein binding faces of the reconstituted GPCR are accessible to bulk solvent

Fig. 2

Structures of lipid headgroups and acyl chains. Chemical structures are shown for lipid headgroup and acyl chain structures that have been used to reconstitute GPCRs in nanodiscs

Fig. 3

Structures of amphipathic polymers. The structures of SMA, SMI, DIBMA and PMA are shown