title: Dynamics of coregulator-induced conformational perturbations in androgen receptor ligand binding domain.
abstract: Androgen receptor (AR) coregulators modulate ligand-induced gene expression in a tissue specific manner. The molecular events that follow coactivator binding to AR and the mechanisms that govern the sequence-specific effects of AR coregulators are poorly understood. Using consensus coactivator sequence D11-FxxLF and biophysical techniques, we show that coactivator association is followed by conformational rearrangement in AR ligand binding domain (AR-LBD) that is enthalpically and entropically favorable with activation energy of 29.8±4.2 kJ/mol. Further characterization of ARA70 and SRC3-1 based consensus sequences reveal that each coactivator induces a distinct conformational state in the dihydrotestosterone:AR-LBD:coactivator complex. Complementary computational modeling revealed that coactivator induced specific alterations in the backbone flexibility of AR-LBD distant from the site of coactivator binding and that the intramolecular rearrangements in AR-LBD backbone induced by the two coactivator peptides were different. These data suggest that coactivators may impart specificity in the transcriptional machinery by changing the steady-state conformation of AR-LBD. These data provide direct evidence that even in the presence of same ligand, AR-LBD can occupy distinct conformational states depending on its interactions with specific coactivators in the tissues. We posit that this coactivator-specific conformational gating may then dictate subsequent binding partners and interaction/affinity for the DNA-response elements.
authors: Section of Endocrinology, Boston University School of Medicine, 670 Albany St., Boston, MA 02118, USA.
authors: Mikhail N
authors: MN
authors: Zakharov
authors: Biju K
authors: BK
authors: Pillai
authors: Shalender
authors: S
authors: Bhasin
authors: Jagadish
authors: J
authors: Ulloor
authors: Andrei Y
authors: AY
authors: Istomin
authors: Chao
authors: C
authors: Guo
authors: Adam
authors: A
authors: Godzik
authors: Raj
authors: R
authors: Kumar
authors: Ravi
authors: R
authors: Jasuja