National Natural Science Foundation of China (NSFC)
81872915
中国
National Natural Science Foundation of China (NSFC)
82073904
中国
National Natural Science Foundation of China (NSFC)
32071203
中国
National Natural Science Foundation of China (NSFC)
81922071
中国
National Natural Science Foundation of China (NSFC)
81773792
中国
National Natural Science Foundation of China (NSFC)
81973373
中国
National Natural Science Foundation of China (NSFC)
21704064
中国
引用
ジャーナル: Nat Commun / 年: 2022 タイトル: Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. 著者: 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 ...著者: 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 / 要旨: 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.
全体 : Cryo-EM structure of the human glucagon-like peptide-1 receptor i...
全体
名称: Cryo-EM structure of the human glucagon-like peptide-1 receptor in complex with non-acylated_tirzepatide and G protein
要素
複合体: Cryo-EM structure of the human glucagon-like peptide-1 receptor in complex with non-acylated_tirzepatide and G protein
タンパク質・ペプチド: Isoform 3 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
タンパク質・ペプチド: Nanobody 35
タンパク質・ペプチド: Non-acylated_tirzepatide
タンパク質・ペプチド: Glucagon-like peptide 1 receptor
タンパク質・ペプチド: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
タンパク質・ペプチド: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
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超分子 #1: Cryo-EM structure of the human glucagon-like peptide-1 receptor i...
超分子
名称: Cryo-EM structure of the human glucagon-like peptide-1 receptor in complex with non-acylated_tirzepatide and G protein タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all
由来(天然)
生物種: Homo sapiens (ヒト)
組換発現
生物種: Spodoptera frugiperda (ツマジロクサヨトウ)
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分子 #1: Isoform 3 of Guanine nucleotide-binding protein G(s) subunit alph...
分子
名称: Isoform 3 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO