7V35

Cryo-EM structure of the GIPR/GLP-1R/GCGR triagonist peptide 20-bound human GCGR-Gs complex

7V35 の概要

• エントリーDOI: 10.2210/pdb7v35/pdb
• EMDBエントリー: 31676
• 分子名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• 機能のキーワード: cryo-electron microscopy; g protein-coupled receptor; ligand recognition; receptor activation; unimolecular agonist, structural protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 158110.49

構造登録者

Zhao, F.h.,Zhou, Q.T.,Cong, Z.T.,Hang, K.N.,Zou, X.Y.,Zhang, C.,Chen, Y.,Dai, A.T.,Liang, A.Y.,Ming, Q.Q.,Wang, M.,Chen, L.N.,Xu, P.Y.,Chang, R.L.,Feng, W.B.,Xia, T.,Zhang, Y.,Wu, B.L.,Yang, D.H.,Zhao, L.H.,Xu, H.E.,Wang, M.W. (登録日: 2021-08-10, 公開日: 2022-03-02, 最終更新日: 2022-03-16)

主引用文献

Zhao, F.,Zhou, Q.,Cong, Z.,Hang, K.,Zou, X.,Zhang, C.,Chen, Y.,Dai, A.,Liang, A.,Ming, Q.,Wang, M.,Chen, L.N.,Xu, P.,Chang, R.,Feng, W.,Xia, T.,Zhang, Y.,Wu, B.,Yang, D.,Zhao, L.,Xu, H.E.,Wang, M.W.
Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors.
Nat Commun, 13:1057-1057, 2022

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 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.

PubMed: 35217653
DOI: 10.1038/s41467-022-28683-0

実験手法

ELECTRON MICROSCOPY (3.4 Å)