Agonism/antagonism switching in allosteric ensembles

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Transcription factor ligands can exhibit dual agonist/antagonist roles, but the underlying structural and molecular mechanisms remain unclear.
• Previous work established that intrinsically disordered (ID) protein folding and population shifts mediate allosteric coupling.

Purpose of the Study:

• To elucidate the mechanism by which a single ligand can function as both an agonist and an antagonist.
• To demonstrate how protein ensemble redistribution tunes function and explains ligand duality.

Main Methods:

• Investigated allosteric systems and protein ensembles.
• Analyzed population redistribution within these systems.
• Examined the role of pre-ligand state probabilities.

Main Results:

• Demonstrated that population redistribution within allosteric systems allows a single ligand to act as both agonist and antagonist.
• Showed this effect is encoded in the protein ensemble, not differential ligand-protein interactions.
• Highlighted the importance of pre-existing state probabilities.

Conclusions:

• Allosteric systems can evolve functional pluripotency, enabling regulation of activity in response to stimuli.
• This ensemble-based mechanism explains the prevalence of intrinsic disorder in transcription factors and cell signaling proteins.
• Provides insights into the energetic principles of site-to-site communication in all allosteric systems.