7FIM

Cryo-EM structure of the tirzepatide (LY3298176)-bound human GLP-1R-Gs complex

Summary for 7FIM

• Entry DOI: 10.2210/pdb7fim/pdb
• EMDB information: 31603
• Descriptor: Nanobody-35, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, ... (6 entities in total)
• Functional Keywords: cryo-electron microscopy; g protein-coupled receptor; ligand recognition; receptor activation; unimolecular agonist, structural protein
• Biological source: synthetic construct; More
• Total number of polymer chains: 6
• Total formula weight: 180596.91

Authors

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. (deposition date: 2021-07-31, release date: 2022-03-02, Last modification date: 2022-03-16)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.4 Å)