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2021.07.29.454286V2.Full.Pdf bioRxiv preprint doi: https://doi.org/10.1101/2021.07.29.454286; this version posted July 31, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Structural basis for the therapeutic advantage of dual and triple agonists 2 at the human GIP, GLP-1 or GCG receptors 3 Fenghui Zhao1,2†, Qingtong Zhou3†, Zhaotong Cong3,†, Kaini Hang4†, Xinyu Zou5†, Chao Zhang4, Yan Chen3, Antao 4 Dai6, Anyi Liang5, Qianqian Ming7, Mu Wang4, Linan Chen7, Peiyu Xu2, Rulue Chang1, Wenbo Feng3, Tian Xia5, Yan 5 Zhang7, Beili Wu2,4,8, Dehua Yang2,6,8*, Lihua Zhao2,8*, H. Eric Xu2,8*, Ming-Wei Wang1,2,3,4,6,8* 6 1School of Pharmacy, Fudan University, Shanghai 201203, China 7 2The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of 8 Sciences, Shanghai 201203, China 9 3Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China 10 4School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. 11 5School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan 430074, 12 China. 13 6The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 14 Shanghai 201203, China. 15 7Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School 16 of Medicine, Hangzhou 310058, China. 17 8University of Chinese Academy of Sciences, Beijing 100049, China. 18 †These authors contributed equally: Fenghui Zhao, Qingtong Zhou, Zhaotong Cong, Kaini Hang, Xinyu Zou. 19 *e-mail: [email protected] (D.H.Y.); [email protected] (L.H.Z.); [email protected] (H.E.X.); 20 [email protected] (M.-W.W) 21 Key words 22 Cryo-electron microscopy; G protein-coupled receptor; ligand recognition; receptor activation; unimolecular agonist 23 Summary 24 Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like 25 peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, 26 GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials 27 to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a 28 GIPR/GLP-1R dualagonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their superior 29 efficacies over monoagonist such as semaglutide, we determined cryo-electron microscopy structures of 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.29.454286; this version posted July 31, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 30 tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR The structures 31 reveal both common and unique features for the dual and triple agonism by illustrating key interactions of 32 clinical relevance at the atomic level. Retention of glucagon function is required to achieve such an advantage 33 over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional 34 versatility and therapeutic supremacy of tirzepatide and peptide 20. 35 Introduction 36 Glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory peptide, GIP), glucagon-like 37 peptide-1 (GLP-1) and glucagon (GCG) are peptide hormones responsible for glucose homeostasis1,2. Their cognate 38 receptors, GIPR, GLP-1R and GCGR, belong to class B1 G protein-coupled receptor (GPCR) family. Successful 39 application of various GLP-1 mimetics to treat type 2 diabetes mellitus (T2DM) and obesity highlights the clinical 40 value of this group of drug targets3. However, development of GIPR- and GCGR-based therapeutics has encountered 41 drawbacks due to the complexity of physiology associated with GIP and GCG4-6. For example, GIP stimulates 42 insulin secretion but also increases GCG levels7,8, while the latter has a parallel role in elevating energy expenditure 43 and blood glucose9. 44 It was reported that the weight loss property (5-10%) of GLP-1 analogs is hampered by dose-dependent 45 side-effects10. Chimeric peptides consisting of amino acids from GIP and GLP-1 were then designed to maximize 46 their metabolic benefits11. Additional consideration was given to GCG for its role in energy expenditure12. Therefore, 47 multi-targeting or unimolecular peptides possessing combinatorial agonism at GIPR, GLP-1R and GCGR have been 48 extensively explored and more than a dozen peptides including two GIPR/GLP-1R dualagonists, ten GLP-1R/GCGR 49 dualagonists and five GIPR/GLP-1R/GCGR triagonists have entered into clinical development (Fig. S1a, 50 Supplementary Table 1)13. Of them, two pioneered unimolecular agonists, tirzepatide (LY3298176) and peptide 20 51 (MAR423) have attracted significant attention from both academic and industrial communities (Fig. 1a). Tirzepatide 52 is an investigational once-weekly GIPR/GLP-1R dualagonist14 with a profound therapeutic superiority in reducing 53 blood glucose and body weight beyond several approved drugs such as semaglutide15 and dulaglutide16 in multiple 54 head-to-head clinical trials. Peptide 20, a GIPR/GLP-1R/GCGR triagonist (currently in phase 1 clinical trial)17 with 55 balanced potency at the three receptors, is evolved from a GLP-1R/GCGR dualagonist18 through iterative sequence 56 refinement and modification (Fig. S1b)14. It reversed glucose dysregulation without detrimental effects on 57 metabolically healthy animals and reduced body weight, lowered fasting blood glucose, decreased glycosylated 58 hemoglobin (HbA1C), improved glucose tolerance, and protected pancreatic islet architecture in diabetic fatty 59 Zucker rats14,19,20. 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.29.454286; this version posted July 31, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 60 To understand molecular mechanisms of the dual and triple agonism conferred by tirzepatide and peptide 20, 61 we determined five cryo-electron microscopy (cryo-EM) structures, including GIPR and GLP-1R bound with 62 tirzepatide and GIPR, GLP-1R and GCGR bound with peptide 20, all in complex with Gs proteins at global 63 resolutions of 3.4 Å, 3.4 Å, 3.1 Å, 3.0 Å and 3.5 Å, respectively. Integrated with pharmacological and clinical data, 64 this work reveal the structural basis of peptide recognition by each receptor and provide important insights into 65 therapeutic benefits resulted from combinatorial agonism. 66 Results 67 Overall structure 68 The tirzepatide–GIPR–Gs, tirzepatide–GLP-1R–Gs, peptide 20–GIPR–Gs, peptide 20–GLP-1R–Gs and peptide 69 20–GCGR–Gs structures were determined by the single-particle cryo-EM approach with overall resolutions of 3.4 Å, 70 3.4 Å, 3.1 Å, 3.0 Å, and 3.5 Å, respectively (Fig. 1b,c, Figs. S2-6, Table S1, Supplementary Figure 1, 71 Supplementary Table 2). Apart from the α-helical domain of Gαs, the presence of bound tirzepatide and peptide 20, 72 individual receptor and heterotrimeric Gs in respective complex was clearly visible in all five EM maps, thereby 73 allowing unambiguous modeling of the secondary structure and side chain orientation of all major components of 74 the complexes (Fig. S6). 75 Tirzepatide has two non-coded amino acid residues at positions 2 and 13 (Aib, α-aminoisobutyric acid), and is 76 acylated on K20P (P indicates that the residue belongs to the peptide) with a γGlu-2×OEG linker and C18 fatty 77 diacid moiety. The first 30 and 29 amino acids of tirzepatide were modelled for the tirzepatide–GIPR–Gs and 78 tirzepatide–GLP-1R–Gs complexes, respectively. 79 Peptide 20 contains two modifications: A2P with Aib and K10P that is covalently attached by a 16-carbon acyl 80 chain (palmitoyl; 16:0) via a gamma carboxylate (γE spacer)14. The γE spacer and palmitic acid (C16:0) were well 81 resolved in the final models of peptide 20–GCGR–Gs and peptide 20–GLP-1R–Gs, while only the γE spacer was 82 modelled for peptide 20–GIPR–Gs with high-resolution features. The first 30, 29, and 28 amino acids of peptide 20 83 were modelled for the peptide 20–GIPR–Gs, peptide 20–GLP-1R–Gs and peptide 20–GCGR–Gs complexes, 84 respectively. 85 As shown in Fig. 2a, the tirzepatide–GIPR–Gs and peptide 20–GIPR–Gs complex structures closely resembled 21 86 that of the GIP–GIPR–Gs complex with Cα root mean square deviation (RMSD) values of 0.5 and 0.4 Å, 87 respectively. Notable conformational differences were observed in the positions of peptide C-terminal half and the 88 surrounding ECL1 and ECD, indicative of GIPR-associated ligand specificity. Through two mutations (M14PL and 89 H18PA), the dense contacts between ECL1 (residues 194 to 211) and GIP were disrupted by peptide 20, as seen from 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.29.454286; this version posted July 31, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
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