Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors

Fenghui Zhao; Qingtong Zhou; Zhaotong Cong; Kaini Hang; Xinyu Zou; Chao Zhang; Yan Chen; Antao Dai; Anyi Liang; Qianqian Ming; Mu Wang; Li-Nan Chen; Peiyu Xu; Rulve Chang; Wenbo Feng; Tian Xia; Yan Zhang; Beili Wu; Dehua Yang; Lihua Zhao; H Eric Xu; Ming-Wei Wang

doi:10.1038/s41467-022-28683-0

Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors

Nat Commun. 2022 Feb 25;13(1):1057. doi: 10.1038/s41467-022-28683-0.

Authors

Fenghui Zhao^#^{1

2}, Qingtong Zhou^#³, Zhaotong Cong^#³, Kaini Hang^#⁴, Xinyu Zou^#⁵, Chao Zhang⁴, Yan Chen³, Antao Dai⁶, Anyi Liang⁵, Qianqian Ming⁷, Mu Wang⁴, Li-Nan Chen⁷, Peiyu Xu², Rulve Chang¹, Wenbo Feng³, Tian Xia⁵, Yan Zhang⁷, Beili Wu^{2

4

8}, Dehua Yang^{9

10

11

12}, Lihua Zhao^{13

14}, H Eric Xu^{15

16}, Ming-Wei Wang^{17

18

19

20

21

22

23}

Affiliations

¹ School of Pharmacy, Fudan University, Shanghai, China.
² The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
³ Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁴ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁵ School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, China.
⁶ The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁷ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁸ University of Chinese Academy of Sciences, Beijing, China.
⁹ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. dhyang@simm.ac.cn.
¹⁰ The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. dhyang@simm.ac.cn.
¹¹ University of Chinese Academy of Sciences, Beijing, China. dhyang@simm.ac.cn.
¹² Research Center for Deepsea Bioresources, Sanya, Hainan, China. dhyang@simm.ac.cn.
¹³ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhaolihuawendy@simm.ac.cn.
¹⁴ University of Chinese Academy of Sciences, Beijing, China. zhaolihuawendy@simm.ac.cn.
¹⁵ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. eric.xu@simm.ac.cn.
¹⁶ University of Chinese Academy of Sciences, Beijing, China. eric.xu@simm.ac.cn.
¹⁷ School of Pharmacy, Fudan University, Shanghai, China. mwwang@simm.ac.cn.
¹⁸ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. mwwang@simm.ac.cn.
¹⁹ Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China. mwwang@simm.ac.cn.
²⁰ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. mwwang@simm.ac.cn.
²¹ The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. mwwang@simm.ac.cn.
²² University of Chinese Academy of Sciences, Beijing, China. mwwang@simm.ac.cn.
²³ Research Center for Deepsea Bioresources, Sanya, Hainan, China. mwwang@simm.ac.cn.

^# Contributed equally.

Abstract

Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dual agonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their multiplexed pharmacological actions over monoagonists such as semaglutide, we determine cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR. The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the near-atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility of tirzepatide and peptide 20.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cryoelectron Microscopy
Diabetes Mellitus, Type 2* / drug therapy
Gastric Inhibitory Polypeptide
Glucagon / metabolism
Glucagon-Like Peptide 1 / therapeutic use
Glucagon-Like Peptide-1 Receptor / metabolism
Glucose / therapeutic use
Humans
Peptides / chemistry
Receptors, G-Protein-Coupled
Receptors, Glucagon*

Substances

Glucagon-Like Peptide-1 Receptor
Peptides
Receptors, G-Protein-Coupled
Receptors, Glucagon
Gastric Inhibitory Polypeptide
Glucagon-Like Peptide 1
Glucagon
Glucose
tirzepatide