Fig. 5. Remodeling of the free-energy landscape of apo R_AB by Rp and the PKA C-subunit explains allosteric pluripotency.

(A) Effect of Rp binding on the ensemble of states accessible to apo R_AB. As the Boltzmann populations of the state decrease, the size of the cartoon is reduced. The inhibitory-competent conformations of R_AB:Rp₂ (red bars) are excited states. (B) Effect of PKA C-subunit binding on the ensemble of states accessible to R_AB:Rp₂. If the binding of the substrate to the kinase is sufficiently weak, and the MgATP level is sufficiently high, the inhibitory states “A_off-B_off” and “A_off-B_on” become the most stable conformations of R_AB in the C:R_AB:Rp₂ ensemble. The kinase is inactive. ΔG_R,gap is the inhibitory excited versus noninhibitory ground state free-energy difference. (C) In the case of substrates that bind C with sufficiently high affinity to compete with R_AB or when the MgATP level decreases, due to the lower effective affinity of R_AB:Rp₂ for C, the most stable conformation of R_AB accessible to the C:R_AB:Rp₂ ensemble is the “A_onB_on” state, which is noninhibitory. Hence, the kinase is active.