8jip

Cryo-EM structure of the GLP-1R/GCGR dual agonist MEDI0382-bound human GLP-1R-Gs complex

spinqualitylabelsall models 8jip, resolution 2.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8jip is a 6 chain structure with sequence from Bos taurus, Escherichia coli, Homo sapiens, Rattus norvegicus and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.85Å Ligands: D6M Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GLP1R_HUMAN This is a receptor for glucagon-like peptide 1. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. Publication Abstract from PubMed Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), two members of class B1 G protein-coupled receptors, play important roles in glucose homeostasis and energy metabolism. They share a high degree of sequence homology but have different functionalities. Unimolecular dual agonists of both receptors developed recently displayed better clinical efficacies than that of monotherapy. To study the underlying molecular mechanisms, we determined high-resolution cryo-electron microscopy structures of GLP-1R or GCGR in complex with heterotrimeric G(s) protein and three GLP-1R/GCGR dual agonists including peptide 15, MEDI0382 (cotadutide) and SAR425899 with variable activating profiles at GLP-1R versus GCGR. Compared with related structures reported previously and supported by our published pharmacological data, key residues responsible for ligand recognition and dual agonism were identified. Analyses of peptide conformational features revealed a difference in side chain orientations within the first three residues, indicating that distinct engagements in the deep binding pocket are required to achieve receptor selectivity. The middle region recognizes extracellular loop 1 (ECL1), ECL2, and the top of transmembrane helix 1 (TM1) resulting in specific conformational changes of both ligand and receptor, especially the dual agonists reshaped ECL1 conformation of GLP-1R relative to that of GCGR, suggesting an important role of ECL1 interaction in executing dual agonism. Structural investigation of lipid modification showed a better interaction between lipid moiety of MEDI0382 and TM1-TM2 cleft, in line with its increased potency at GCGR than SAR425899. Together, the results provide insightful information for the design and development of improved therapeutics targeting these two receptors simultaneously. Structural analysis of the dual agonism at GLP-1R and GCGR.,Li Y, Zhou Q, Dai A, Zhao F, Chang R, Ying T, Wu B, Yang D, Wang MW, Cong Z Proc Natl Acad Sci U S A. 2023 Aug 15;120(33):e2303696120. doi: , 10.1073/pnas.2303696120. Epub 2023 Aug 7. PMID:37549266 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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