Recognition and accommodation at the androgen receptor coactivator binding interface.
Prostate cancer is a leading killer of men in the industrialized world. Underlying this disease is the aberrant action of the androgen receptor (AR). AR is distinguished from other nuclear receptors in that after hormone binding, it preferentially responds to a specialized set of coactivators bearing aromatic-rich motifs, while responding poorly to coactivators bearing the leucine-rich "NR box" motifs favored by other nuclear receptors. Under normal conditions, interactions with these AR-specific coactivators through aromatic-rich motifs underlie targeted gene transcription. However, during prostate cancer, abnormal association with such coactivators, as well as with coactivators containing canonical leucine-rich motifs, promotes disease progression. To understand the paradox of this unusual selectivity, we have derived a complete set of peptide motifs that interact with AR using phage display. Binding affinities were measured for a selected set of these peptides and their interactions with AR determined by X-ray crystallography. Structures of AR in complex with FxxLF, LxxLL, FxxLW, WxxLF, WxxVW, FxxFF, and FxxYF motifs reveal a changing surface of the AR coactivator binding interface that permits accommodation of both AR-specific aromatic-rich motifs and canonical leucine-rich motifs. Induced fit provides perfect mating of the motifs representing the known family of AR coactivators and suggests a framework for the design of AR coactivator antagonists.
Graduate Group in Biophysics, University of California, San Francisco, California, USA.
Eugene
E
Hur
Samuel J
SJ
Pfaff
E Sturgis
ES
Payne
Hanne
H
Grøn
Benjamin M
BM
Buehrer
Robert J
RJ
Fletterick
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D007700:Kinetics; D060588:LIM Domain Proteins; D007930:Leucine / Q000737:chemistry; D008297:Male; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry; D051958:Nuclear Receptor Coactivator 2 / Q000737:chemistry; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins / Q000737:chemistry; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011944:Receptors, Androgen / Q000737:chemistry*; D011960:Receptors, Estrogen / Q000737:chemistry; D011965:Receptors, Glucocorticoid / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance; D037042:Thyroid Hormone Receptors beta / Q000737:chemistry; D013997:Time Factors; D014157:Transcription Factors / Q000737:chemistry
C410798:AR protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C491310:GRIP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C498001:NCOA2 protein, human; C111382:NCOA4 protein, human; D009419:Nerve Tissue Proteins; D051958:Nuclear Receptor Coactivator 2; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D019151:Peptide Library; D010455:Peptides; C118499:RNF14 protein, human; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; C490351:TGFB1I1 protein, human; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D007930:Leucine