The transcriptional activity of androgen receptor (AR) is regulated by the sequential binding of various ligands (e.g., dihydrotestosterone, DHT) and coactivators (e.g., SRC/p160) to the AR ligand binding domain (LBD) (Askew et al., J Biol Chem 2007;282:25801–25816, Lee and Chang, Cell Mol Life Sci 2003;60:1613–1622). However, the synergism between the recruitments of coactivator (SRC 2–3) and ligand (such as DHT) to AR at atomic level remains unclear. Thus, in this work, extensive explicit-solvent molecular dynamics (MD) simulations on four independent trajectories, that is, AR-apo (unbound), DHT·AR, AR·SRC, and DHT·AR·SRC, are performed to investigate the potential communications between the two events in the AR transcriptional process. The MD simulations, analysis of the dynamical cross-correlation maps, comparisons of the binding energy, and thermodynamic analysis reveal a definite structural and functional link between Activation Function-2 (AF-2) surface and the ligand binding site influenced by the binding of ligand and coactivator to the LBD: (I) The DHT binding can increase the LBD volume to 753.0 Å3 from its compact ligand-free state (372.1 Å3), resulting in a group of helices (1, 2, 8, and loop 2′) to move outward and exert added traction on the ligand binding pathway, which subsequently leads to rearrange the AF-2 region to well recruit the SRC; (II) Similarly, the SRC recruitment is also found to facilitate the ligand binding through transmitting a concomitant push-pull effort from the AF-2 surface to the DHT binding site, leading to the opening of entrance to the LBD formed by Val684, Met745, and Arg752, increase of the volume of binding pocket (896.4 Å3) and stabilization of the dynamic structure of the LBD. These results, in a dynamic form, initially show a bidirectional structural and functional relay between the bound DHT and SRC that establishes AR functional potency. Proteins 2011. © 2011 Wiley-Liss, Inc.
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