Biophysical Society Conference | Tahoe 2024

Molecular Biophysics of Membranes

Wednesday Speaker Abstracts

MODULATION OF CLASS B1 GPCRS BY THE PLASMA MEMBRANE ENVIRONMENT Kin Chao 1,3 ; Linda Wong 2 ; Affiong Oqua 2 ; Jas Kalayan 3 ; James Gebbie-Rayet 3 ; Alejandra Tomas 2 ; Sarah L. Rouse 1 ; 1 Imperial College London, Life Sciences, London, United Kingdom 2 Imperial College London, Metabolism, Digestion and Reproduction, London, United Kingdom 3 Science and Technology Facilities Council, Scientific Computing Department, Daresbury, United Kingdom Class B1 GPCRs are key targets for prevalent diseases, but existing peptide drugs targeting these receptors have limitations, requiring the development of novel small molecules, particularly of allosteric modulators with greater potential to fine-tune receptor outputs. GPCR-lipid binding sites represent a large, untapped opportunity for allosteric drug development, but our understanding of lipid modulation of Class B1 GPCRs remains limited. We present molecular dynamics simulations of all 15 Class B1 family members in model plasma membranes, allowing us to determine patterns of specific lipid interactions across this subfamily. We observe that GM3 plays a modulatory role in the dynamics of the extracellular domain (ECD), in a GPCR state-dependent manner. We further assess in vitro the impact of GM3 on GLP1R ECD conformational dynamics using a TR-FRET GM3 inhibitor Eliglustat assay.

39