State-selective frustration as a key driver of allosteric pluripotency.

Allosteric pluripotency arises when an allosteric effector switches from agonist to antagonist depending on the experimental conditions. For example, the Rp-cAMPS ligand of Protein Kinase A (PKA) switches from agonist to antagonist as the MgATP concentration increases and/or the kinase substrate affinity or concentration decreases. Understanding allosteric pluripotency is essential to design effective allosteric therapeutics with minimal side effects. Allosteric pluripotency of PKA arises from divergent allosteric responses of two homologous tandem cAMP-binding domains, resulting in a free energy landscape for the Rp-cAMPS-bound PKA regulatory subunit R1a in which the ground state is kinase inhibition-incompetent and the kinase inhibition-competent state is excited. The magnitude of the free energy difference between the ground non-inhibitory and excited inhibitory states (ΔG R,Gap) relative to the effective free energy of R1a binding to the catalytic subunit of PKA (ΔG R:C) dictates whether the antagonism-to-agonism switch occurs. However, the key drivers of ΔG R,Gap are not fully understood. Here, by analyzing an R1a mutant that selectively silences allosteric pluripotency, we show that a major determinant of ΔG R,Gap unexpectedly arises from state-selective frustration in the ground inhibition-incompetent state of Rp-cAMPS-bound R1a. Such frustration is caused by steric clashes between the phosphate-binding cassette and the helices preceding the lid, which interact with the phosphate and base of Rp-cAMPS, respectively. These clashes are absent in the excited inhibitory state, thus reducing the ΔG R,Gap to values comparable to ΔG R:C, as needed for allosteric pluripotency to occur. The resulting model of allosteric pluripotency is anticipated to assist the design of effective allosteric modulators. This journal is © The Royal Society of Chemistry.

Citation

Jung Ah Byun, Bryan VanSchouwen, Nishi Parikh, Madoka Akimoto, Eric Tyler McNicholl, Giuseppe Melacini. State-selective frustration as a key driver of allosteric pluripotency. Chemical science. 2021 Sep 01;12(34):11565-11575

PMID: 34667558

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