Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone
Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone
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DOI：
10.1074/jbc.m703268200
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发表时间：
2007-08-31
影响因子：
4.8
通讯作者：
Wilson, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Askew, Emily B.;Gampe, Robert T., Jr.;Wilson, Elizabeth M.
雄激素受体（AR）通过与睾酮(T)或其5 α还原代谢物双氢睾酮（DHT）的高亲和力结合而转录激活，双氢睾酮是男性生殖道发育所需的更有效的雄激素。通过测定野生型AR和前列腺癌体细胞突变体与AR FXXLF或辅激活剂LXXLL肽络合的T结合配体结合域晶体结构，研究了T活性较弱的分子基础。AR配体结合口袋中T和DHT几乎相同的相互作用与含有配体结合域的AR片段的相似解离率相关。然而，T诱导较弱的AR FXXLF和辅激活子LXXLL基序在激活功能2 （AF2）上的相互作用。FXXLF基序与AF2结合的效率较低，导致T与全长AR的解离更快。然而，T可以通过AR螺旋-10 H874Y前列腺癌突变获得dht样活性。Tyr-874突变体侧链介导了一个从外部螺旋-10到骨干蛋白核心螺旋- 4残基Tyr-739的新的氢键机制，通过改善FXXLF和LXXLL基序的AF2结合来挽救t诱导的AR活性。黑色素瘤抗原基因蛋白-11是一种结合AR FXXLF基序并靶向AF2激活的AR共调节因子，通过改善核心螺旋相互作用提高AR AF2活性。我们得出结论，由于T依赖性AR FXXLF和辅激活子LXXLL基序在AF2上的相互作用不太有利，因此T是比DHT弱的雄激素。
The androgen receptor (AR) is transcriptionally activated by high affinity binding of testosterone ( T) or its 5 alpha-reduced metabolite, dihydrotestosterone (DHT), a more potent androgen required for male reproductive tract development. The molecular basis for the weaker activity of T was investigated by determining T-bound ligand binding domain crystal structures of wild-type AR and a prostate cancer somatic mutant complexed with the AR FXXLF or coactivator LXXLL peptide. Nearly identical interactions of T and DHT in the AR ligand binding pocket correlate with similar rates of dissociation from an AR fragment containing the ligand binding domain. However, T induces weaker AR FXXLF and coactivator LXXLL motif interactions at activation function 2 (AF2). Less effective FXXLF motif binding to AF2 accounts for faster T dissociation from full-length AR. T can nevertheless acquire DHT-like activity through an AR helix-10 H874Y prostate cancer mutation. The Tyr-874 mutant side chain mediates a new hydrogen bonding scheme from exterior helix-10 to backbone protein core helix- 4 residue Tyr-739 to rescue T-induced AR activity by improving AF2 binding of FXXLF and LXXLL motifs. Greater AR AF2 activity by improved core helix interactions is supported by the effects of melanoma antigen gene protein-11, an AR coregulator that binds the AR FXXLF motif and targets AF2 for activation. We conclude that T is a weaker androgen than DHT because of less favorable T-dependent AR FXXLF and coactivator LXXLL motif interactions at AF2.