He Bin, Gampe Robert T, Kole Adam J, Hnat Andrew T, Stanley Thomas B, An Gang, Stewart Eugene L, Kalman Rebecca I, Minges John T, Wilson Elizabeth M
Laboratories for Reproductive Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Mol Cell. 2004 Nov 5;16(3):425-38. doi: 10.1016/j.molcel.2004.09.036.
The androgen receptor (AR) is required for male sex development and contributes to prostate cancer cell survival. In contrast to other nuclear receptors that bind the LXXLL motifs of coactivators, the AR ligand binding domain is preferentially engaged in an interdomain interaction with the AR FXXLF motif. Reported here are crystal structures of the ligand-activated AR ligand binding domain with and without bound FXXLF and LXXLL peptides. Key residues that establish motif binding specificity are identified through comparative structure-function and mutagenesis studies. A mechanism in prostate cancer is suggested by a functional AR mutation at a specificity-determining residue that recovers coactivator LXXLL motif binding. An activation function transition hypothesis is proposed in which an evolutionary decline in LXXLL motif binding parallels expansion and functional dominance of the NH(2)-terminal transactivation domain in the steroid receptor subfamily.
雄激素受体（AR）是男性性发育所必需的，并且有助于前列腺癌细胞的存活。与其他结合共激活因子LXXLL基序的核受体不同，AR配体结合结构域优先与AR FXXLF基序进行结构域间相互作用。本文报道了结合和未结合FXXLF及LXXLL肽的配体激活的AR配体结合结构域的晶体结构。通过比较结构功能和诱变研究确定了建立基序结合特异性的关键残基。在一个特异性决定残基处的功能性AR突变恢复了共激活因子LXXLL基序结合，这提示了前列腺癌中的一种机制。提出了一种激活功能转变假说，即LXXLL基序结合的进化性下降与类固醇受体亚家族中NH(2)-末端反式激活结构域的扩展和功能优势并行。
