Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors.
Journal, issue, pages	Nat Commun, Vol. 13, Issue 1, Page 1057, Year 2022
Publish date	Feb 25, 2022
Authors	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 /
PubMed 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 ...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.
External links	Nat Commun / PubMed:35217653 / PubMed Central
Methods	EM (single particle)
Resolution	3.0 - 3.5 Å
Structure data	31603 7fim EMDB-31603, PDB-7fim: Cryo-EM structure of the tirzepatide (LY3298176)-bound human GLP-1R-Gs complex Method: EM (single particle) / Resolution: 3.4 Å 31604 7fin EMDB-31604, PDB-7fin: Cryo-EM structure of the GIPR/GLP-1R/GCGR triagonist peptide 20-bound human GIPR-Gs complex Method: EM (single particle) / Resolution: 3.1 Å 31606 7fiy EMDB-31606, PDB-7fiy: Cryo-EM structure of the tirzepatide-bound human GIPR-Gs complex Method: EM (single particle) / Resolution: 3.4 Å 31676 7v35 EMDB-31676, PDB-7v35: Cryo-EM structure of the GIPR/GLP-1R/GCGR triagonist peptide 20-bound human GCGR-Gs complex Method: EM (single particle) / Resolution: 3.5 Å 31836 7vab EMDB-31836, PDB-7vab: Cryo-EM structure of the non-acylated tirzepatide (LY3298176)-bound human GIPR-Gs complex Method: EM (single particle) / Resolution: 3.2 Å 31879 7vbh EMDB-31879, PDB-7vbh: Cryo-EM structure of the GIPR/GLP-1R/GCGR triagonist peptide 20-bound human GLP-1R-Gs complex Method: EM (single particle) / Resolution: 3.0 Å 31880 7vbi EMDB-31880, PDB-7vbi: Cryo-EM structure of the non-acylated tirzepatide (LY3298176)-bound human GLP-1R-Gs complex Method: EM (single particle) / Resolution: 3.0 Å
Chemicals	ChemComp-CLR: CHOLESTEROL ChemComp-GGL: GAMMA-L-GLUTAMIC ACID ChemComp-D6M: N-hexadecanoyl-L-glutamic acid
Source	homo sapiens (human) synthetic construct (others) rattus norvegicus (Norway rat) bos taurus (cattle) escherichia coli (E. coli)
Keywords	STRUCTURAL PROTEIN / Cryo-electron microscopy; G protein-coupled receptor; ligand recognition; receptor activation; unimolecular agonist