Cryo-EM structures of the human CaS receptor. The active structures include the PAM-bound (A) and PAM-free (B) states; the inactive structure is in the NAM-bound form (C). For each structure, the cryo-EM density map (Left) and cartoon representation (Right) are oriented toward the TM–homodimer interface. (Discontinuous densities below a size threshold of 2 voxels were removed from map display.) Subunits are individually colored blue and cyan, and TM helices are numbered. Ligands bound to the active CaS receptor include TNCA (dark gray), Ca2+ (green), PO43− (orange and red), and R-568 in the PAM-bound state (yellow). Additional molecules present are N-linked glycans (NAG; light gray) and CLR (pink). In the inactive state, only the NAM NPS-2143 (salmon) was modeled.