Structural mechanism of ligand activation in human calcium-sensing receptor
Yong Geng,
Lidia Mosyak,
Igor Kurinov,
Hao Zuo,
Emmanuel Sturchler,
Tat Cheung Cheng,
Prakash Subramanyam,
Alice P Brown,
Sarah C Brennan,
Hee-chang Mun,
Martin Bush,
Yan Chen,
Trang X Nguyen,
Baohua Cao,
Donald D Chang,
Matthias Quick,
Arthur D Conigrave,
Henry M Colecraft,
Patricia McDonald,
Qing R Fan
Affiliations
Yong Geng
Department of Pharmacology, Columbia University, New York, United States; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Lidia Mosyak
Department of Pharmacology, Columbia University, New York, United States
Igor Kurinov
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, United States
Hao Zuo
Department of Pharmacology, Columbia University, New York, United States
Emmanuel Sturchler
Department of Molecular Therapeutics, The Scripps Translational Science Institute, Jupiter, United States
Tat Cheung Cheng
Department of Pharmacology, Columbia University, New York, United States
Prakash Subramanyam
Department of Physiology and Cellular Biophysics, Columbia University, New York, United States
Alice P Brown
School of Life and Environmental Sciences, University of Sydney, New South Wales, Australia
Sarah C Brennan
School of Life and Environmental Sciences, University of Sydney, New South Wales, Australia
Hee-chang Mun
School of Life and Environmental Sciences, University of Sydney, New South Wales, Australia
Martin Bush
Department of Pharmacology, Columbia University, New York, United States
Yan Chen
Department of Pharmacology, Columbia University, New York, United States
Trang X Nguyen
Department of Psychiatry, Columbia University, New York, United States
Baohua Cao
Department of Pharmacology, Columbia University, New York, United States
Donald D Chang
Department of Physiology and Cellular Biophysics, Columbia University, New York, United States
Matthias Quick
Department of Psychiatry, Columbia University, New York, United States
Arthur D Conigrave
School of Life and Environmental Sciences, University of Sydney, New South Wales, Australia
Henry M Colecraft
Department of Physiology and Cellular Biophysics, Columbia University, New York, United States
Patricia McDonald
Department of Molecular Therapeutics, The Scripps Translational Science Institute, Jupiter, United States
Department of Pharmacology, Columbia University, New York, United States; Department of Pathology and Cell Biology, Columbia University, New York, United States
Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that maintains extracellular Ca2+ 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 Ca2+ and PO43- ions. Both ions are crucial for structural integrity of the receptor. While Ca2+ ions stabilize the active state, PO43- ions reinforce the inactive conformation. The activation mechanism of CaSR involves the formation of a novel dimer interface between subunits.