9E2A
Glucagon Like Peptide Receptor-1 (GLP1R) A316T mutant with GLP-1 peptide. Dominant negative Gs complex.
Summary for 9E2A
| Entry DOI | 10.2210/pdb9e2a/pdb |
| EMDB information | 47447 |
| Descriptor | Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total) |
| Functional Keywords | gpcr, glp1, glp-1r, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 6 |
| Total formula weight | 167300.47 |
| Authors | Deane-Alder, K.,Belousoff, M.J.,Wootten, D.L. (deposition date: 2024-10-22, release date: 2025-10-29, Last modification date: 2026-02-18) |
| Primary citation | El Eid, L.,Manchanda, Y.,Austin, G.,Deane-Alder, K.,Rujan, R.M.,Mariam, Z.,Oqua, A.I.,Belousoff, M.J.,de la Serna, J.B.,Sloop, K.W.,Rutter, G.A.,Montoya, A.,Withers, D.J.,Millership, S.J.,Bouzakri, K.,Jones, B.,Reynolds, C.A.,Sexton, P.M.,Wootten, D.,Deganutti, G.,Tomas, A. In vivo functional profiling and structural characterization of the human GLP1R A316T variant. Sci Adv, 12:eadw0899-eadw0899, 2026 Cited by PubMed Abstract: 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. PubMed: 41637494DOI: 10.1126/sciadv.adw0899 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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