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TitleIn vivo functional profiling and structural characterization of the human A316T variant.
Journal, issue, pagesSci Adv, Vol. 12, Issue 6, Page eadw0899, Year 2026
Publish dateFeb 6, 2026
AuthorsLiliane El Eid / Yusman Manchanda / Gregory Austin / Kieran Deane-Alder / Roxana-Maria Rujan / Zamara Mariam / Affiong I Oqua / Matthew J Belousoff / Jorge Bernardino de la Serna / Kyle W Sloop / Guy A Rutter / Alex Montoya / Dominic J Withers / Steven J Millership / Karim Bouzakri / Ben Jones / Christopher A Reynolds / Patrick M Sexton / Denise Wootten / Giuseppe Deganutti / Alejandra Tomas /
PubMed AbstractGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective therapies for type 2 diabetes (T2D) and obesity, yet patient responses are variable, with gene variation potentially linked to ...Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective therapies for type 2 diabetes (T2D) and obesity, yet patient responses are variable, with gene variation potentially linked to therapeutic outcomes. A natural missense variant, A316T, protects against T2D and cardiovascular disease. Here, we generated and characterized a human A316T mouse model. Human mice displayed lower fasting blood glucose versus wild-type littermates even under metabolic stress, as well as slower weight gain and alterations in islet cytoarchitecture, glucagon secretion, and liver metabolism under a high-fat, high-sucrose diet. This was however associated with blunted responses to pharmacological GLP-1RAs in vivo. Further investigations in β cell models demonstrated that human A316T exhibits characteristics of constitutive activation but dampened GLP-1RA responses. Results are further supported by cryo-EM analyses and molecular dynamics simulations of GLP-1R A316T structure, collectively demonstrating that the A316T variant governs basal GLP-1R activity and pharmacological responses to GLP-1R-targeting therapies.
External linksSci Adv / PubMed:41637494
MethodsEM (single particle)
Resolution3.3 Å
Structure data

47447

9e2a

EMDB-47447, PDB-9e2a:
Glucagon Like Peptide Receptor-1 (GLP1R) A316T mutant with GLP-1 peptide. Dominant negative Gs complex.
Method: EM (single particle) / Resolution: 3.3 Å

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsMEMBRANE PROTEIN / GPCR / GLP1 / GLP-1R

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