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Abstract: The calcium-sensing receptor (CaSR) plays a central role in maintaining systemic calcium homeostasis. In the treatment of secondary hyperparathyroidism (SHPT) associated with chronic kidney disease (CKD), CaSR is targeted by calcimimetic drugs. Recent cryo-electron microscopy (Cryo-EM) studies have begun to reveal how CaSR is modulated by various allosteric modulators and signals through G proteins. However, the mechanisms of CaSR activation by the novel calcimimetic, upacicalcet, and the aminoglycoside antibiotic, neomycin, remain elusive. In this study, we present high-resolution cryo-EM structures of human CaSR homodimer complexed with either upacicalcet or neomycin. Coupled with functional studies, it is revealed that both drugs target the extracellular region of the receptor. upacicalcet occupies the amino-acid binding site of the Venus Flytrap (VFT) domain promoting VFT closure, whereas neomycin occupies a calcium-binding site at the homodimer interface at the base of the VFT, thus inducing the proximity of the two protomers. These findings reveal distinct molecular mechanisms of CaSR modulation by drug molecules, highlight the diversity of ligand-dependent regulatory modes, and provide a structural foundation for the rational design of future CaSR-targeting therapeutics.