Asymmetric activation of the calcium-sensing receptor homodimer

Journal article

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 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.

Authors: Gao, Y; Robertson, MJ; Rahman, SN; Seven, AB; Zhang, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature
• Volume: 595
• Issue: 7867
• Pages: 455-459
• Publication date: 2021-06-30
• Acceptance date: 2021-06-03
• DOI: 10.1038/s41586-021-03691-0
• EISSN: 1476-4687
• ISSN: 0028-0836
• Pmid: 34194040
• Language: English
• Keywords: models, molecular; peptides; calcium; humans; receptors, calcium-sensing; FFR; cryoelectron microscopy; substrate specificity; protein binding; protein multimerization