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
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2116506119

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 (GLP-1R). In addition to GIPR signaling, the pathway bias at the GLP-1R may contribute to the efficacy of tirzepatide at improving glucose control and body weight regulation in type 2 diabetes mellitus. To investigate the structural basis for the differential signaling of tirzepatide, mechanistic pharmacology studies were allied with cryogenic electron microscopy. Here, we report high-resolution structures of tirzepatide in complex with the GIPR and GLP-1R. Similar to the native ligands, tirzepatide adopts an α-helical conformation with the N terminus reaching deep within the transmembrane core of both receptors. Analyses of the N-terminal tyrosine (Tyr1Tzp) of tirzepatide revealed a weak interaction with the GLP-1R. Molecular dynamics simulations indicated a greater propensity of intermittent hydrogen bonding between the lipid moiety of tirzepatide and the GIPR versus the GLP-1R, consistent with a more compact tirzepatide–GIPR complex. Informed by these analyses, tirzepatide was deconstructed, revealing a peptide structure–activity relationship that is influenced by acylation-dependent signal transduction. For the GIPR, Tyr1Tzp and other residues making strong interactions within the receptor core allow tirzepatide to tolerate fatty acid modification, yielding an affinity equaling that of GIP. Conversely, high-affinity binding with the extracellular domain of the GLP-1R, coupled with decreased stability from the Tyr1Tzp and the lipid moiety, foster biased signaling and reduced receptor desensitization. Together, these studies inform the structural determinants underlying the function of tirzepatide.