8xzi

Cryo-EM structure of the CMF-019-bound human APLNR-Gi complex

spinqualitylabelsall models 8xzi, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8xzi is a 5 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.7Å Ligands: A1D5N Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the beta-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-G(i1) complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications. Structure-based design of non-hypertrophic apelin receptor modulator.,Wang WW, Ji SY, Zhang W, Zhang J, Cai C, Hu R, Zang SK, Miao L, Xu H, Chen LN, Yang Z, Guo J, Qin J, Shen DD, Liang P, Zhang Y, Zhang Y Cell. 2024 Mar 14;187(6):1460-1475.e20. doi: 10.1016/j.cell.2024.02.004. Epub , 2024 Feb 29. PMID:38428423 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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