7m3j

Publication Abstract from PubMed

The 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.