Human class B1 GPCR modulation by plasma membrane lipids

Abstract

The class B1 G protein-coupled receptor (GPCR) subfamily is a class of receptors known for their regulatory roles in metabolism and neuronal activity and as important drug targets. Lipids play key functional roles in modulation of GPCR signalling, yet our understanding of the molecular level detail of specific lipid interactions with class B1 GPCRs remains limited. Here we present coarse-grained molecular dynamics (MD) simulations of the active and inactive states of 15 human class B1 family members and use aiida-gromacs to capture full provenance for the set-up of simulations in complex plasma membranes. Receptors exhibit state-dependent lipid interactions with the regulatory sterol cholesterol and phospholipid phosphatidylinositiol-3,4-bisphosphate (PIP2) at defined locations on the receptor surface. Global analysis of trends across the subfamily reveals conserved patterns of lipid interaction dynamics. The glycosphingolipid GM3 exerts a modulatory influence on the dynamics of class B1 extracellular domains in both simulations and in vitro time-resolved FRET assays.