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Updated: May 23, 2026

Measurements of Physiological Stress Responses in C. Elegans
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Published on: May 21, 2020

GLP-1R R131Q links long-range conformational remodeling to cellular stress phenotypes.

Takashi Kato1, Noriko Inomata1, Keiko Serizawa1

  • 1Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Journal of Molecular Graphics & Modelling
|May 21, 2026
PubMed
Summary
This summary is machine-generated.

The GLP-1R R131Q variant alters receptor structure and function, impacting pancreatic cell behavior and mitochondrial responses. This study reveals how genetic variations affect GLP-1 receptor activity.

Keywords:
GLP-1 receptorMitochondriaMolecular dynamicsPrincipal component analysisR131QiPSC-derived β cells

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Biophysics

Background:

  • Glucagon-like peptide-1 receptor (GLP-1R) agonists exhibit significant inter-individual efficacy variability.
  • The structural basis for how common GLP-1R variants influence receptor behavior is not well understood.

Purpose of the Study:

  • To investigate the structural and functional consequences of the GLP-1R R131Q variant.
  • To elucidate the impact of this variant on receptor dynamics and cellular phenotypes in human pancreatic models.

Main Methods:

  • All-atom molecular dynamics simulations of wild-type (WT) and R131Q variants in ligand-free and GLP-1-bound states.
  • Principal component analysis and residue-centered analysis of simulation data.
  • Assessment of the R131Q variant in isogenic human induced pluripotent stem cell (iPSC)-derived pancreatic models.

Main Results:

  • The R131Q variant induced distinct conformational changes in both ligand-free and GLP-1-bound states, affecting local anchoring and receptor-peptide interactions.
  • Molecular mechanics/Generalized Born surface area (MM/GBSA) analysis indicated weaker GLP-1 binding energetics for the R131Q variant.
  • In iPSC-derived pancreatic cells, the R131Q variant was associated with enhanced β-cell maturity markers and improved mitochondrial, antioxidant, and stress-response readouts.

Conclusions:

  • The GLP-1R R131Q variant rewires receptor conformational ensembles in a state-dependent manner.
  • These structural alterations correlate with significant mitochondrial and stress-response phenotypes in human pancreatic models.
  • Findings support a model where genetic variants modulate GLP-1R signaling pathways with functional consequences for pancreatic cell function.