8月15日，国际杂志《生化期刊》（Biochemical Journal）发表了中科院上海生科院生物化学与细胞生物学研究所丁建平研究组关于核糖体S6激酶1 (ribosome protein subunit 6 kinase 1，S6K1) 功能调控机制的最新研究成果，该研究成果得到同行审稿专家和杂志编辑的赞赏。
mTOR信号通路在细胞生长、增殖以及代谢调控等生物学过程中发挥重要作用，其功能异常与肿瘤、代谢疾病以及发育缺陷等密切相关。丁建平组长期从事mTOR信号通路调控的分子机制研究，取得了一系列重要成果。S6K1是mTORC1的下游效应分子之一，通过磷酸化多种底物参与众多生理过程的调控，包括基因转录、mRNA剪接以及蛋白质合成等。S6K1的激酶活性受到自身多个位点磷酸化修饰的调控，包括疏水模体（HM）上Thr389和活化环区Thr229的磷酸化，但其分子机制并不清楚。
丁建平组博士生王建船等人解析了6个S6K1催化结构域自身及其融合HM区域与特异小分子抑制剂形成的复合物的晶体结构。结构分析表明，HM通过疏水和亲水相互作用结合在N-lobe的疏水性口袋中，其中两个高度保守的氨基酸残基Gln140和Arg121，在亲水相互作用网络中发挥重要作用，稳定了催化结构域的构象。进一步的生化和细胞生物学实验结果显示，体内S6K1上Thr389的磷酸化可在Th229未磷酸化时进行，而且Thr389的磷酸化或者模拟磷酸化的突变体能够通过氢键增强HM与N-lobe的相互作用。此外，还发现活化环区上存在一个非典型的、可能为S6K1特有的锌指结构域，为S6K1的调节机制研究提供了新思路。研究结果进一步加深了对S6K1调控机制的理解，同时还为设计和改造S6K1特异性的小分子抑制剂提供了线索。
该课题得到了国家科技部、国家自然科学基金委、中国科学院和上海市科委的经费支持。（生物谷Bioon.com）
doi:10.1042/BJ20121863
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Crystal structures of S6K1 provide insights into the regulation mechanism of S6K1 by the hydrophobic motif.
Wang J, Zhong C, Wang F, Qu F, Ding J.
The activity of S6K1 (p70 ribosomal protein subunit 6 kinase 1) is stimulated by phosphorylation of Thr389 in the hydrophobic motif by mTORC1 (mammalian target of rapamycin complex 1) and phosphorylation of Thr229 in the activation loop by PDK1 (phosphoinositide-dependent kinase 1); however, the order of the two events is still ambiguous. In the present paper we report six crystal structures of the S6K1 kinase domain alone or plus the hydrophobic motif in various forms, in complexes with a highly specific inhibitor. The structural data, together with the biochemical data, reveal in vivo phosphorylation of Thr389 in the absence of Thr229 phosphorylation and demonstrate the importance of two conserved residues, Gln140 and Arg121, in the establishment of a hydrogen-bonding network between the N-lobe (N-terminal lobe) and the hydrophobic motif. Phosphorylation of Thr389 or introduction of a corresponding negatively charged group leads to reinforcement of the network and stabilization of helix αC. Furthermore, comparisons of S6K1 with other AGC (protein kinase A/protein kinase G/protein kinase C) family kinases suggest that the structural and sequence differences in the hydrophobic motif and helix αC account for their divergence in PDK1 dependency. Taken together, the results of the present study indicate that phosphorylation of the hydrophobic motif in S6K1 is independent of, and probably precedes and promotes, phosphorylation of the activation loop.
