Extended Data Fig. 10 |. Schematic of CaSR activation mechanism.

In the inactive state, CaSR is relatively flexible and the 7TMs are separated facing each other at the TM5-TM6 plane. The VFTs adopt inactive open-open/closed conformations. The open-closed conformation can be stabilized by aromatic amino acids (AAs) or their derivatives, thus priming the receptor for activation. NAM binds at both 7TMs with the same conformation and locks the TM6 toggle switch in an inactive conformation. Under high Ca²⁺ and high Trp conditions, the ECD adopts a closed-closed active conformation, while the presence of the NAM prevents the 7TMs from adopting the active asymmetric configuration. Upon activation by high Ca²⁺ concentration, the VFTs adopt an active closed-closed conformation, which is stabilized by L-Trp bound at the cleft of each VFT and the ECD PAM etelcalcetide further stabilizes the interface between LB2 of the closed-closed VFTs. Closure of the VFTs leads to rearrangement of the CRDs, bringing the 7TMs together to form an asymmetric TM6-TM6 interface. The asymmetric configuration is stabilized by 7TM PAMs adopting distinct poses. The 7TM with a bent PAM is more tilted than the opposing 7TM with its C terminus sequestered in the membrane, and likely unable to couple to G protein.