Open AccessStructural determinants of dual incretin receptor agonism by tirzepatide
Author(s) -
Bingfa Sun,
Francis S. Willard,
Dan Feng,
Jorge AlsinaFernandez,
Qi Chen,
Michał Vieth,
Joseph Ho,
Aaron D. Showalter,
Cynthia Stutsman,
Liyun Ding,
Todd M. Suter,
James D. Dunbar,
John W. Carpenter,
Faiz Ahmad Mohammed,
Eitaro Aihara,
Robert A. Brown,
Ana B. Bueno,
Paul J. Emmerson,
Julie S. Moyers,
Tong Sun Kobilka,
Matthew P. Coghlan,
Brian K. Kobilka,
Kyle W. Sloop
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2116506119
Subject(s) - incretin , agonist , receptor , g protein coupled receptor , endogenous agonist , endocrinology , glucagon like peptide 1 receptor , medicine , chemistry , pharmacology , biochemistry , biology , diabetes mellitus , type 2 diabetes , dopamine receptor d1
Significance Tirzepatide 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.