(A) Cα trace of inactive structure with elements involved in homodimer formation highlighted by cartoons. The interface is divided into three regions I, II, and IV. Site II is further separated into two symmetrical parts II_a and II_b. Specific contacts at each interface region are shown in surrounding panels. Dashed lines indicate hydrogen bonds. (B) Cα trace of active structure showing elements involved in homodimer formation. The interface is divided into six regions, I, II, III, IV, V, and VI. Specific contacts at the interface areas III, IV, V, and VI are shown in surrounding panels. For both structures, the domains involved in dimerization at each interface region are: I: LB1-LB1; II: LB1-LB1; III: LB2-LB1; IV: LB2-LB2; V: LB2-CR; VI: CR-CR. (C) Dose-dependent Ca2+-stimulated IP accumulation in cells transiently expressing wild-type (wt) or mutant CaSR. Naturally occurring inactivating mutations L159P, R172G, D215G, R227L, R551K, and G557E are located at the homodimer interface. The single mutation W458A was designed based on structure to affect receptor homodimerization.