7M3G

Asymmetric Activation of the Calcium Sensing Receptor Homodimer

Summary for 7M3G

• Entry DOI: 10.2210/pdb7m3g/pdb
• EMDB information: 23654
• Descriptor: Extracellular calcium-sensing receptor, etelcalcetide, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: gpcr, calcium sensing receptor, active state, positive allosteric modulator, family c gpcr, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 210058.86

Authors

Gao, Y.,Robertson, M.J.,Zhang, C.,Meyerowitz, J.G.,Panova, O.,Skiniotis, G. (deposition date: 2021-03-18, release date: 2021-06-30, Last modification date: 2024-11-20)

Primary citation

Gao, Y.,Robertson, M.J.,Rahman, S.N.,Seven, A.B.,Zhang, C.,Meyerowitz, J.G.,Panova, O.,Hannan, F.M.,Thakker, R.V.,Brauner-Osborne, H.,Mathiesen, J.M.,Skiniotis, G.
Asymmetric activation of the calcium-sensing receptor homodimer.
Nature, 595:455-459, 2021

PubMed Abstract: The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders. CaSR is a family C G-protein-coupled receptor that functions as an obligate homodimer, with each protomer composed of a Ca-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 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.

PubMed: 34194040
DOI: 10.1038/s41586-021-03691-0

Experimental method

ELECTRON MICROSCOPY (2.5 Å)