Structural basis of androgen receptor binding to selective androgen response elements.

Area of Science:

• Molecular Biology
• Structural Biology
• Endocrinology

Background:

• Steroid receptors typically bind DNA as dimers to inverted repeat sequences (IR3).
• Selective androgen response elements (ADR3) with direct repeat motifs have been identified.
• Understanding the structural basis of androgen receptor (AR) DNA binding is crucial for deciphering gene regulation.

Purpose of the Study:

• To elucidate the 3D crystal structure of the androgen receptor (AR) DNA-binding domain bound to a selective ADR3 element.
• To compare the AR DNA-binding mode with other steroid receptors.
• To identify structural features responsible for AR's selective DNA binding.

Main Methods:

• X-ray crystallography was used to determine the 3D structure of the AR DNA-binding domain complexed with an ADR3 DNA sequence.
• Structural analysis focused on the dimer interface and DNA binding geometry.
• Comparison of AR structural data with existing data for other steroid receptors, such as the glucocorticoid receptor.

Main Results:

• The AR DNA-binding domain adopted an unexpected head-to-head dimer arrangement on the ADR3 element.
• This contrasts with the head-to-tail arrangement observed in other nuclear receptors bound to similar DNA structures.
• The AR dimer interface exhibits additional stabilizing interactions compared to other steroid receptors, enhancing affinity for nonconsensus elements like ADR3.

Conclusions:

• The unique head-to-head dimerization of the AR DNA-binding domain is key to its selective recognition of ADR3 elements.
• Enhanced interfacial stability in AR contributes to its ability to bind noncanonical response elements.
• These findings provide structural insights into the selective gene regulation mediated by the androgen receptor.