Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide

Abstract

The global prevalence of type 2 diabetes and obesity, affecting over 507 million 1 and 890 million 2 individuals, respectively, underscores the urgent need for more effective treatments. The most successful treatments currently available include glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), exemplified by semaglutide (approved in 2017, $19.9 billion sales in 2023) 3 and tirzepatide (approved in 2022, $5.3 billion sales in 2023) 4 . Unlike semaglutide which solely activates GLP-1R (one of the three pivotal receptors regulating glucose homeostasis), tirzepatide also activates glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) to enhance metabolic benefits with reduced side-effects 5 . However, both medications do not target glucagon (GCG) receptor (GCGR). Recently, retatrutide (also known as LY3437943) 6 , 7 , 8 , 9 has shown impressive efficacy in obesity treatment through triple agonism at GLP-1R, GIPR and GCGR. Compared to the corresponding endogenous hormones, retatrutide is more potent at GIPR by a factor of 8.9, and less potent at GCGR and GLP-1R by factors of 0.3 and 0.4, respectively 7 (Fig. 1a ). Retatrutide induces greater body weight losses in obese mice than tirzepatide, due to an increased energy expenditure through GCGR activation 6 . In a phase 2 obesity trial, retatrutide demonstrated an average weight loss of 17.5% at 24 weeks and 24.2% at 48 weeks in the 12 mg dose group 7 . Additionally, in a phase 2 trial targeting type 2 diabetes, retatrutide demonstrated significant improvements in glycemic control and substantial weight reduction, maintaining a safety profile comparable to certain approved GLP-1RAs 8 (Supplementary Table S1 ). These results support the rationale of developing retatrutide as an alternative to semaglutide and/or tirzepatide 5 . Indeed, phase 3 clinical trials of retatrutide for type 2 diabetes, non-alcoholic fatty liver disease, and obesity are presently underway (Supplementary Table S2 ) 10 . To understand the multiplexed pharmacological actions of retatrutide, we used cryo-electron microscopy (cryo-EM) to determine the structures of GLP-1R, GIPR and GCGR bound to retatrutide. Fig. 1: Molecular recognition of retatrutide by GLP-1R, GIPR and GCGR. a Retatrutide (LY3437943) possesses combinatorial agonism at GLP-1R, GIPR and GCGR, distinct from the approved GLP-1R agonists (such as semaglutide and exenatide) and GLP-1R/GIPR dual agonist tirzepatide. b Cryo-EM maps of retatrutide-bound GLP-1R (left), GIPR (middle) and GCGR (right) in complex with G s . The colored cryo-EM density maps are shown at the thresholds of 0.110, 0.107 and 0.134 for the retatrutide–GLP-1R–G s , retatrutide–GIPR–G s and retatrutide–GCGR–G s complexes, respectively. The GLP-1R is shown in dodger blue, GIPR in forest green, GCGR in hot pink, GLP-1R-bound retatrutide in gold, GIPR-bound retatrutide in orange, GCGR-bound retatrutide in coral, Gα s in yellow, Gβ subunit in cyan, Gγ subunit in blue and Nb35 in gray. c Structural comparison of retatrutide–GLP-1R, retatrutide–GIPR and retatrutide–GCGR. Receptor ECD and G protein are omitted for clarity. d Schematic diagram of retatrutide recognition mode in GLP-1R, GIPR and GCGR, described by fingerprint strings encoding different interaction types of the surrounding residues in each receptor. Close-up views of the interactions are shown for the N-terminal nine residues of retatrutide. The polar contacts are shown as black dashed lines. Receptor residues are labeled with class B1 GPCR numbering and colored sky blue for salt bridge, red for hydrogen bond, orange for stacking and gray for hydrophobic interactions. Residues that show no interaction with retatrutide are displayed as white circles. e Effects of GLP-1R (top), GIPR (middle), and GCGR (bottom) mutations on retatrutide-induced cAMP accumulation. Bars represent differences in the calculated retatrutide potency (pEC 50 ) for representative mutants relative to the wild-type (WT). Data are colored according to the extent of effect. Data shown are from at least three independent experiments performed in quadruplicate. All data were analyzed by one-way ANOVA and Dunnett’s test. * P < 0.05, ** P < 0.01, *** P < 0.001, and **** P < 0.0001. N.D., values that could not be determined due to incomplete curve fits. f The distinct secondary structures of the ECL1 of GLP-1R, GIPR and GCGR. g Amino acid sequence comparison of endogenous hormones, representative dual and triple agonists. Residues are colored according to sequence conservation among GLP-1, GIP and GCG. Aib α-amino isobutyric acid, αMeL α-methyl L -leucine. Semaglutide, tirzepatide, peptide 20 (MAR423) and retatrutide are acylated with various fatty diacid moieties via a linker connected to the lysine residues at the positions of 20, 20, 10 and 17, respectively. h Comparison of the interactions between GLP-1R ECL1 and representative peptide agonists including retatrutide, GLP-1 (PDB ID: 6X18), semaglutide (PDB ID: 7KI0), exenatide (PDB ID: 7LLL), tirzepatide (PDB ID: 7FIM) and peptide 20 (PDB ID: 7VBH). i Comparison of the interactions between GIPR ECL1 and representative peptide agonists including retatrutide, GIP (PDB ID: 7DTY), tirzepatide (PDB ID: 7FIY) and peptide 20 (PDB ID: 7FIN). j Comparison of the interactions between GCGR ECL1 and representative peptide agonists including retatrutide, GCG (PDB ID: 6LMK) and peptide 20 (PDB ID: 7V35). Full size image

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