8szf
From Proteopedia
Cryo-EM structure of cinacalcet-bound active-state human calcium-sensing receptor CaSR in lipid nanodiscs
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 PubMedThe calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor(1) (GPCR) that has a central role in regulating systemic calcium homeostasis(2,3). Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional G(i) versus G(q) proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both G(i) and G(q) drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein-lipid interactions. Selective G(i) and G(q) coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR-G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid L-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands. Allosteric modulation and G-protein selectivity of the Ca(2+)-sensing receptor.,He F, Wu CG, Gao Y, Rahman SN, Zaoralova M, Papasergi-Scott MM, Gu TJ, Robertson MJ, Seven AB, Li L, Mathiesen JM, Skiniotis G Nature. 2024 Feb;626(8001):1141-1148. doi: 10.1038/s41586-024-07055-2. Epub 2024 , Feb 7. PMID:38326620[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Gao Y | He F | Skiniotis G | Wu C
