7RA3

cryo-EM of human Gastric inhibitory polypeptide receptor GIPR bound to GIP

Summary for 7RA3

• Entry DOI: 10.2210/pdb7ra3/pdb
• EMDB information: 24334
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-3,Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Single-chain variable fragment 16, ... (7 entities in total)
• Functional Keywords: class b gpcr, glucagon-like peptide-1 receptor, g protein nucleotide exchange factor., membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 196865.96

Authors

Sun, B.,Kobilka, B.K.,Sloop, K.W.,Feng, D.,Kobilka, T.S. (deposition date: 2021-06-29, release date: 2022-04-13, Last modification date: 2024-10-30)

Primary citation

Sun, B.,Willard, F.S.,Feng, D.,Alsina-Fernandez, J.,Chen, Q.,Vieth, M.,Ho, J.D.,Showalter, A.D.,Stutsman, C.,Ding, L.,Suter, T.M.,Dunbar, J.D.,Carpenter, J.W.,Mohammed, F.A.,Aihara, E.,Brown, R.A.,Bueno, A.B.,Emmerson, P.J.,Moyers, J.S.,Kobilka, T.S.,Coghlan, M.P.,Kobilka, B.K.,Sloop, K.W.
Structural determinants of dual incretin receptor agonism by tirzepatide.
Proc.Natl.Acad.Sci.USA, 119:e2116506119-e2116506119, 2022

PubMed Abstract: SignificanceTirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), which are incretin receptors that regulate carbohydrate metabolism. This investigational agent has proven superior to selective GLP-1R agonists in clinical trials in subjects with type 2 diabetes mellitus. Intriguingly, although tirzepatide closely resembles native GIP in how it activates the GIPR, it differs markedly from GLP-1 in its activation of the GLP-1R, resulting in less agonist-induced receptor desensitization. We report how cryogenic electron microscopy and molecular dynamics simulations inform the structural basis for the unique pharmacology of tirzepatide. These studies reveal the extent to which fatty acid modification, combined with amino acid sequence, determines the mode of action of a multireceptor agonist.

PubMed: 35333651
DOI: 10.1073/pnas.2116506119

Experimental method

ELECTRON MICROSCOPY (3.24 Å)