Poster Presentation The 48th Lorne Conference on Protein Structure and Function 2023

A clinically-relevant mutation of glucagon-like peptide 1 receptor alters extracellular loop dynamics (#214)

Kieran Deane-Alder 1 , Matthew Belousoff 1 2 , Emma Dal Maso 1 2 , Denise Wootten 1 2 , Patrick Sexton 1 2
  1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia
  2. ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash University, Melbourne, Victoria, Australia

The glucagon-like peptide 1 receptor (GLP-1R) is a class B1 (secretin-like) G protein-coupled receptor (GPCR) and a key regulator of postprandial blood glucose (1). Because of its critical role in insulin secretion, GLP-1R has been a major drug target for the treatment of type 2 diabetes mellitus (T2DM), a metabolic disease that is driven by both reduced presence of blood insulin, and the development of tolerance to the glucose-lowering effect of the hormone (2). Several exogenous GLP-1R agonist peptides have become important drugs for the treatment of T2DM.

 Polymorphisms of the GLP-1R have been observed and may be clinically relevant (3,4). A large exome chip study revealed that the A316T single nucleotide polymorphism (SNP) of GLP-1R is present in the population with a minor allele frequency of 1.4% (5). Individuals with this SNP had significantly reduced prevalence of T2DM and lower fasting glucose, suggesting a protective effect. However, it was also found that the A316T subgroup had reduced early insulin secretion, and higher glucose 2 hours after oral challenge. While affinity for the endogenous GLP-1 hormone is not significantly improved, a recent pre-print study found that the A316T mutation improved coupling to Gs in a reductionist assay (6,7).

 To enhance understanding of the molecular mechanism of this clinically-relevant mutation, we obtained a 3.3 Å cryo-EM structure of GLP-1R (A316T) in complex with G proteins and GLP-1, the major endogenous ligand. 3D variance analysis revealed increased dynamics in the extracellular loops, which are known to be important for peptide affinity and Gs-coupled modes of signalling (8). This enhanced movement may underlie pharmacological and physiological differences observed for the A316T SNP.

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