Nuclear receptor proteins are ligand-dependent transcription factors implicated in a multitude of physiological phenomena, as well as disease. In the canonical mechanism of activation, large-scale conformational change occurs in response to ligand binding.  This induces co-activator protein recruitment and triggers the complex events leading to gene transcription. In addition, recent discoveries have shown that phosphorylation of nuclear receptors provides an additional level of regulation. In particular, upon phosphorylation of the RARa ligand binding domain, there is an increase in the affinity for cyclin H, which is part of the CAK complex. Within the CAK complex, the kinase CDK-2 phosphorylates the N-terminal domain of the same nuclear receptor protein, as necessary step towards gene transcription. Using molecular dynamics simulations, we characterize the structural and dynamical consequences of nuclear receptor phosphorylation. This leads us to suggest a molecular mechanism for allosteric signal transduction in nuclear receptor proteins.

Allostery in nuclear receptor proteins: Molecular mechanisms from molecular dynamics simulations

244th National Meeting (2012)

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