Structural features discriminate androgen receptor N/C terminal and coactivator interactions

► AR transcriptional activity depends on the androgen-dependent interaction of the AR LBD AF2 surface with FXXLF and LXXLL motifs. ► AR function is influenced by AR AF2 germline mutations that cause androgen insensitivity and by somatic mutations that arise in prostate cancer. ► An extended region of helix 12 outside the AF2 binding cleft participates in FXXLF and LXXLL motif binding. ► Stabilization of the AR LBD core by somatic mutations in prostate cancer increases AR transcriptional activity. ► AR LBD surface residues Gln-902, Tyr-739 and Lys-905 provide structural flexibility needed to accommodate FXXLF or LXXLL motif binding.