Homology Modeling of the Calcium Sensing Receptor Extracellular Domain

The extracellular calcium-sensing receptor (CaR) on the parathyroid cell surface negatively regulates secretion of parathyroid hormone (PTH). CaR has an important rule in diseases. Cinacalcet hydrochloride, an allosteric agonist of this receptor was approved by FDA in 2004 for treatment of secondary hyperparathyroidism. Cinacalcet is indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma or for secondary hyperparathyroidism in patients with chronic kidney disease who require dialysis. This drug is an allosteric agonist which is bind to transmembrane domain of CaR. Studies showed that the ligand binding region of CaR, as expected, is located at the amino-terminal domain (extracellular domain). There is no crystal structure or model is available for this domain of CaR so we constructed the model and found putative ligand binding site. This model will be useful for finding new CaR orthosteric ligands and designing new drugs.