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Helix 1/8 Interactions Influence the Activity of Nuclear Receptor Ligand-Binding Domains

Nuclear Receptor Discovery Research, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709-3398

Address all correspondence and requests for reprints to: Andrew Billin, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709-3398. E-mail: andrew.n.billin{at}gsk.com.

The ligand-binding domain (LBD) of apo-nuclear receptors in solution is thought to be a very dynamic structure with many possible conformations. Upon ligand binding, the structure is stabilized to a more rigid conformation. The dynamic stabilization assay is a LBD reassembly assay that takes advantage of the high specificity of the intramolecular interactions that comprise the ligand-bound LBD. Here, we demonstrate dynamic stabilization for the nuclear receptors peroxisome proliferator-activated receptor (PPAR) and nerve growth factor inducible (NGFIB)ß and identify residues important for stabilization of the intramolecular interactions induced by PPAR ligands. Site-directed mutagenesis studies identified residues in helices 1 and 8 required for LBD reassembly. Further, disrupting the helix 1/8 interaction in the context of the holo-LBD alters the response of the receptor in a compound-specific manner, suggesting that residues far from the ligand-binding pocket can influence the stability of the ligand-bound receptor. Thus, these results support and extend models of the apo-LBD of PPAR as a dynamic structure.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARγ  |  NGFIB

Ligands:   GW 1929  |  Rosiglitazone

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