An interpretation of positional displacement of the helix12 in nuclear receptors: preexistent swing-up motion triggered by ligand binding

Abstract

Positional displacement of helix12 (H12) in the estrogen receptor alpha, which belongs to the nuclear receptor (NR) superfamily, is studied by the molecular dynamics (MD) simulation and the linear response theory. Tendency of the H12 to swing up upon ligand binding, which is consistent with X-ray structures and earlier MD simulations, is reproduced by the calculation of the conformational fluctuation in apo state and the response to the external perturbation. Our study thus provides an interpretation of the positional change of the H12 such that it is derived by the preexistent swing-up motion where the ligand binding works only as a trigger. Our finding, which illustrates underlying mechanism of the H12 motion, would contribute to finding a way to regulate the transcriptional activity by synthesized ligands because the transcriptional activity of the NR is governed by the position of the H12.