2. Academic Validation
  3. Structural mechanism of ligand activation in human calcium-sensing receptor

Structural mechanism of ligand activation in human calcium-sensing receptor

  • Elife. 2016 Jul 19;5:e13662. doi: 10.7554/eLife.13662.
Yong Geng 1 2,  Lidia Mosyak 1,  Igor Kurinov 3,  Hao Zuo 1,  Emmanuel Sturchler 4,  Tat Cheung Cheng 1,  Prakash Subramanyam 5,  Alice P Brown 6,  Sarah C Brennan 6,  Hee-Chang Mun 6,  Martin Bush 1,  Yan Chen 1,  Trang X Nguyen 7,  Baohua Cao 1,  Donald D Chang 5,  Matthias Quick 7,  Arthur D Conigrave 6,  Henry M Colecraft 5,  Patricia McDonald 4,  Qing R Fan 1 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, Columbia University, New York, United States.
  • 2 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 3 Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United States.
  • 4 Department of Molecular Therapeutics, The Scripps Translational Science Institute, Jupiter, United States.
  • 5 Department of Physiology and Cellular Biophysics, Columbia University, New York, United States.
  • 6 School of Life and Environmental Sciences, University of Sydney, New South Wales, Australia.
  • 7 Department of Psychiatry, Columbia University, New York, United States.
  • 8 Department of Pathology and Cell Biology, Columbia University, New York, United States.
PMID: 27434672 DOI: 10.7554/eLife.13662
Abstract

Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that maintains extracellular CA(2+) homeostasis through the regulation of parathyroid hormone secretion. It functions as a disulfide-tethered homodimer composed of three main domains, the Venus Flytrap module, cysteine-rich domain, and seven-helix transmembrane region. Here, we present the crystal structures of the entire extracellular domain of CaSR in the resting and active conformations. We provide direct evidence that L-amino acids are agonists of the receptor. In the active structure, L-Trp occupies the orthosteric agonist-binding site at the interdomain cleft and is primarily responsible for inducing extracellular domain closure to initiate receptor activation. Our structures reveal multiple binding sites for CA(2+) and PO4(3-) ions. Both ions are crucial for structural integrity of the receptor. While CA(2+) ions stabilize the active state, PO4(3-) ions reinforce the inactive conformation. The activation mechanism of CaSR involves the formation of a novel dimer interface between subunits.

Keywords

amino acids; biochemistry; biophysics; calcium-sensing receptor; extracellular calcium homeostasis; extracellular domain structure; human; principal agonist; receptor activation mechanism; structural biology.

Figures