Fig. 6.

The transition model can predict the action of pharmacological modulators. (A) A thermodynamic cycle for a dimeric ligand (see Fig. 4A) and an inhibitor which blocks dimerization, but does not directly interfere with ligand binding. This inhibitor is assumed to bind to the dimerization interface and thus prevent receptor dimerization; it only binds to unliganded monomers (M) and liganded monomer (ML). (B) A thermodynamic cycle for a dimeric ligand and an inhibitor which competes with ligand binding, but does not directly interfere with dimerization. This inhibitor is assumed to bind to the ligand binding interface and thus prevent ligand binding; it only binds to unliganded monomers (M) and dimers (D). (C) & (D) Predictions of the effect of the two different inhibitors on theliganded dimeric fraction. The black curve is the case of no inhibitor, and the blue and red curves correspond to (A) and (B), respectively. (C) The liganded dimeric fraction as a function of inhibitor concentration, where the ligand concentration is 1 nM; the dashed magenta line indicates an inhibitor concentration of 1 nM. (D) The liganded dimeric fraction as a function of ligand concentration, where the inhibitor concentration is 1 nM; the dashed magenta line indicates a ligand concentration of 1 nM. In all cases, receptor concentration is 500 rec/μm², K1 = .029 μm²/rec, L1 = 9.6*10⁷ M⁻¹, and Λ2 = 4.3*10⁹ M⁻¹; for the blue curve, I1 = I2 = 1.5*10⁹ M⁻¹ and for the red curve, I1 = 9.6*10⁷ M⁻¹ and I2 = 4.3*10⁹ M⁻¹.