Structural determinants of dual incretin receptor agonism by tirzepatide

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 13; pp. 1 - 11
• Main Authors: Sun, Bingfa, Willard, Francis S., Feng, Dan, Alsina-Fernandez, Jorge, Chen, Qi, Vieth, Michal, Ho, Joseph D., Showalter, Aaron D., Stutsman, Cynthia, Ding, Liyun, Suter, Todd M., Dunbar, James D., Carpenter, John W., Mohammed, Faiz Ahmad, Aihara, Eitaro, Brown, Robert A., Bueno, Ana B., Emmerson, Paul J., Moyers, Julie S., Kobilka, Tong Sun, Coghlan, Matthew P., Kobilka, Brian K., Sloop, Kyle W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.03.2022
• Subjects: Acylation; Adenosine monophosphate; Affinity; Bias; Biological Sciences; Body weight; Conformation; Cyclic AMP; Desensitization; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Electron microscopy; Fatty acids; Gastric Inhibitory Polypeptide - metabolism; Gastric Inhibitory Polypeptide - pharmacology; Gastric Inhibitory Polypeptide - therapeutic use; GIP protein; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor - metabolism; Glucose; Humans; Hydrogen bonding; Incretins - pharmacology; Lipids; Molecular dynamics; Peptides; Pharmacology; Polypeptides; Receptors; Receptors, Gastrointestinal Hormone - agonists; Receptors, Gastrointestinal Hormone - metabolism; Receptors, Gastrointestinal Hormone - therapeutic use; Signal transduction; Signaling; Tyrosine; G protein coupled receptor (GPCR); GIP receptor; tirzepatide; GLP-1 receptor; structure

Tirzepatide (LY3298176) is a fatty-acid-modified, dual incretin receptor agonist that exhibits pharmacology similar to native GIP at the glucose-dependent insulinotropic polypeptide receptor (GIPR) but shows bias toward cyclic adenosine monophosphate signaling at the glucagon-like peptide-1 receptor...