Dynamics of coregulator-induced conformational perturbations in androgen receptor ligand binding domain

Area of Science:

• Molecular biology
• Biochemistry
• Structural biology

Background:

• Androgen receptor (AR) coregulators are crucial for modulating ligand-induced gene expression.
• The precise molecular mechanisms governing AR coregulator function and sequence-specific effects remain incompletely understood.

Purpose of the Study:

• To investigate the molecular events following coactivator binding to the AR ligand-binding domain (AR-LBD).
• To elucidate the mechanisms by which AR coregulators induce sequence-specific effects on AR conformation and function.

Main Methods:

• Utilized consensus coactivator sequences (D11-FxxLF) and biophysical techniques to study AR-LBD conformational changes.
• Employed computational modeling to analyze coactivator-induced alterations in AR-LBD backbone flexibility.
• Characterized specific coactivator consensus sequences (ARA70 and SRC3-1).

Main Results:

• Coactivator association triggers an enthalpically and entropically favorable conformational rearrangement in the AR-LBD, with an activation energy of 29.8±4.2 kJ/mol.
• Distinct coactivators (ARA70, SRC3-1) induce unique conformational states in the dihydrotestosterone:AR-LBD:coactivator complex.
• Computational modeling revealed coactivator-specific alterations in AR-LBD backbone flexibility, distant from the binding site.

Conclusions:

• Coactivators may confer specificity to the transcriptional machinery by altering the steady-state conformation of the AR-LBD.
• AR-LBD can adopt distinct conformational states even with the same ligand, dependent on specific coactivator interactions within tissues.
• Coactivator-specific conformational gating likely dictates subsequent binding partners and DNA-response element interaction affinity.