Computational Modeling of the Structural Mechanism Linking Ligand and Corepressor Binding to Thyroid Hormone Receptors

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Thyroid hormone receptors (TRs) are nuclear receptors with two functional states. Upon binding to the thyroid hormone, TRs recruit coactivator proteins and activate gene transcription. Without the hormone ligands, TRs interact with corepressor proteins and repress transcription. Due to the importance of the thyroid hormone action in embryo development, metabolism, heart rhythm and cholesterol level, the molecular mechanism behind the functional switch has been studied extensively. However, the current available crystal structures of thyroid hormone receptor ligand binding domains (LBDs) are all in the ligand-bound (holo) form, with no revelation on ligand-free (apo) form or transcription corepressor bound form. In order to elucidate the complete apo to holo switch process, we constructed homology models of apo TR from the available apo structures of interrelated nuclear receptors: retinoid acid receptor (RXR) and peroxisome proliferators activated receptor (PPAR). Both models were subjected to energy minimization followed by molecular dynamic (MD) simulation. Analysis of the MD simulations proved that the model based on PPAR was more stable than the model based on RXR. As a result, unlike the prevailing idea that TRs would exert a major structural change in the C-terminal activation helix (AF2) domain upon ligand binding, TRs exhibit only subtle changes at the AF2 domain. Our model predicts that the recruitment of corepressor proteins, which require the relocation of the AF2 domain, is more appropriately portrayed as an induced fit process. Additionally, we constructed homology models of TR LBD in complex with the nuclear receptor interacting domains of corepressor proteins. Molecular dynamic simulation of this receptor-correpressor complex system in the absence or presence of the ligand thyroid hormone has identified correlated conformational changes that may be important for the functional switch.