Asymmetric activation of the calcium-sensing receptor homodimer.

ABSTRACT: The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca²⁺, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders¹. CaSR is a family C G-protein-coupled receptor² that functions as an obligate homodimer, with each protomer composed of a Ca²⁺-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 Ca²⁺ and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protom

SUBMITTER: Gao Y 

PROVIDER: S-EPMC8826748 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature