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Agonism/antagonism switching in allosteric ensembles
Hesam N. Motlagh and Vincent J. Hilser
Proceedings of the National Academy of Sciences of the United States of America
Vol. 109, No. 11 (March 13, 2012), pp. 4134-4139
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/41507108
Page Count: 6
You can always find the topics here!Topics: Ligands, Agonists, Proteins, Architecture, Thermodynamics, Transcription factors, Free energy, Communication disorders, Binding sites, Agonism
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Ligands for several transcription factors can act as agonists under some conditions and antagonists under others. The structural and molecular bases of such effects are unknown. Previously, we demonstrated how the folding of intrinsically disordered (ID) protein sequences, in particular, and population shifts, in general, could be used to mediate allosteric coupling between different functional domains, a model that has subsequently been validated in several systems. Here it is shown that population redistribution within allosteric systems can be used as a mechanism to tune protein ensembles such that a given ligand can act as both an agonist and an antagonist. Importantly, this mechanism can be robustly encoded in the ensemble, and does not require that the interactions between the ligand and the protein differ when it is acting either as an agonist or an antagonist. Instead, the effect is due to the relative probabilities of states prior to the addition of the ligand. The ensemble view of allostery that is illuminated by these studies suggests that rather than being seen as switches with fixed responses to allosteric activation, ensembles can evolve to be "functionally pluripotent," with the capacity to up or down regulate activity in response to a stimulus. This result not only helps to explain the prevalence of intrinsic disorder in transcription factors and other cell signaling proteins, it provides important insights about the energetic ground rules governing site-to-site communication in all allosteric systems.
Proceedings of the National Academy of Sciences of the United States of America © 2012 National Academy of Sciences