9j7i
Cryo-EM Structure of calcium sensing receptor in complex gamma-glutamyl-valyl-glycine as a kokumi substance
Structural highlights
DiseaseCASR_HUMAN Autosomal dominant hypocalcemia;Familial isolated hypoparathyroidism due to impaired PTH secretion;Neonatal severe primary hyperparathyroidism;Familial hypocalciuric hypercalcemia type 1;Bartter syndrome with hypocalcemia. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Homozygous defects in CASR can be a cause of primary hyperparathyroidism in adulthood. Patients suffer from osteoporosis and renal calculi, have marked hypercalcemia and increased serum PTH concentrations. FunctionCASR_HUMAN Senses changes in the extracellular concentration of calcium ions. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. Publication Abstract from PubMedTaste is a key element for food palatability and is strongly influenced by the five basic tastes and other taste sensations, such as fatty orosensation, and koku perception, which indicates taste complexity, mouthfulness and lastingness. This study focuses on the taste modifier gamma-glutamyl-valyl-glycine (gamma-EVG), a potent kokumi substance that enhances taste and koku perception by modulating the calcium-sensing receptor (CaSR). We used cryo-electron microscopy to determine the structure of the CaSR/gamma-EVG complex at a resolution of 3.55 A. Structural analysis revealed important interactions between gamma-EVG and the CaSR, involving key residues, such as Pro39, Phe42, Arg66, Ser147, and Glu297. Mutagenesis experiments demonstrated the importance of these residues in peptide binding. Each gamma-EVG residue contributed to its binding to the orthosteric ligand binding site of the CaSR. These findings elucidate the molecular basis of kokumi peptide recognition by the CaSR and contribute to a better understanding of positive allosteric modulators of the CaSR. In addition, this research provides valuable insights into the functionality of class C G-protein-coupled receptors in taste perception, potentially informing the development of new taste modifiers and advancing the field of food science. Cryo-EM structure of the calcium-sensing receptor complexed with the kokumi substance gamma-glutamyl-valyl-glycine.,Yamaguchi H, Kitajima S, Suzuki H, Suzuki S, Nishikawa K, Kamegawa A, Fujiyoshi Y, Takahashi K, Tagami U, Maruyama Y, Kuroda M, Sugiki M Sci Rep. 2025 Jan 31;15(1):3894. doi: 10.1038/s41598-025-87999-1. PMID:39890873[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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