7m3g
Asymmetric Activation of the Calcium Sensing Receptor Homodimer
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), a cell-surface sensor for Ca(2+), is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders(1). CaSR is a family C G-protein-coupled receptor(2) that functions as an obligate homodimer, with each protomer composed of a Ca(2+)-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca(2+) and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor. Asymmetric activation of the calcium-sensing receptor homodimer.,Gao Y, Robertson MJ, Rahman SN, Seven AB, Zhang C, Meyerowitz JG, Panova O, Hannan FM, Thakker RV, Brauner-Osborne H, Mathiesen JM, Skiniotis G Nature. 2021 Jun 30. pii: 10.1038/s41586-021-03691-0. doi:, 10.1038/s41586-021-03691-0. PMID:34194040[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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