Allosteric Control of Cofactor Binding to Nuclear Hormone Receptors

Abstract

The nuclear receptor superfamily (NRs) comprises ligand-dependent transcription regulators, many of which function as homodimers or heterodimers with RXR. We show that addition of an SRC-1 coactivator-derived peptide to monomeric liganded retinoic acid receptor (RAR) promotes efficient homodimer formation. X-ray crystallography revealed that homodimers are asymmetrical, reminiscent of functional RXR-RAR heterodimers with distinct conformations of ligand in the two subunits. A global switch to the dimeric state with a 2RAR:1SRC-1 stoichiometry was also seen using a larger 20kDa domain of SRC-1. Our study reveals an allosteric mechanism whereby coactivator binding to one RAR partner affects ligand conformation and H12 position of the second partner, hrough the dimer interface. A similar control on the recruitment of SRC-1 is also observed with ER in the crystal structures of ERa bound to agonist ligands and coactivator peptide.