Insights into the inhibition of the p90 ribosomal S6 kinase (RSK) by the flavonol glycoside SL0101 from the 1.5 Å crystal structure of the N-terminal domain of RSK2 with bound inhibitor.
Insights into the inhibition of the p90 ribosomal S6 kinase (RSK) by the flavonol glycoside SL0101 from the 1.5 Å crystal structure of the N-terminal domain of RSK2 with bound inhibitor.
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DOI：
10.1021/bi300620c
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发表时间：
2012-08-21
期刊：
影响因子：
2.9
通讯作者：
Derewenda ZS
中科院分区：
文献类型：
--
作者：
Utepbergenov D;Derewenda U;Olekhnovich N;Szukalska G;Banerjee B;Hilinski MK;Lannigan DA;Stukenberg PT;Derewenda ZS
P90核糖体S6家族(RSK)是潜在的药物靶点，因为它们参与了癌症和其他病理过程。目前只有两种已知的RSK选择性抑制剂，但选择性的基础尚不清楚。其中一种抑制剂是一种天然存在的山奈酚-α-L-二乙酰鼠李糖苷，SL0101。在这里，我们报道了RSK2异构体的N-末端激酶结构域与SL0101的复合体的晶体结构。与核苷酸结合形式相比，精炼的原子模型揭示了蛋白质部分前所未有的结构重组。整个N-叶、铰链区和αD-螺旋经历了戏剧性的构象变化，导致核苷酸结合位点的重排，同时形成了一个高度疏水的口袋，在空间上适合容纳SL0101。这些意想不到的结果将对进一步优化SL0101支架作为一类新型激酶抑制剂的有前景的先导药物具有非常重要的价值。
The p90 ribosomal S6 family of kinases (RSK) are potential drug targets, due to their involvement in cancer and other pathologies. There are currently only two known selective inhibitors of RSK, but the basis for selectivity is not known. One of these inhibitors is a naturally occurring kaempferol-α-L-diacetylrhamnoside, SL0101. Here, we report the crystal structure of the complex of the N-terminal kinase domain of the RSK2 isoform with SL0101 at 1.5 Å resolution. The refined atomic model reveals unprecedented structural reorganization of the protein moiety, as compared to the nucleotide-bound form. The entire N-lobe, the hinge region and the αD-helix undergo dramatic conformational changes resulting in a rearrangement of the nucleotide binding site with concomitant formation of a highly hydrophobic pocket spatially suited to accommodate SL0101. These unexpected results will be invaluable in further optimization of the SL0101 scaffold as a promising lead for a novel class of kinase inhibitors.
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影响因子：
16
作者：
Eisinger-Mathason, T. S. Karin;Andrade, Josefa;Groehler, Angela L.;Clark, David E.;Muratore-Schroeder, Tara L.;Pasic, Lejla;Smith, Jeffrey A.;Shabanowitz, Jeffrey;Hunt, Donald F.;Macara, Ian G.;Lannigan, Deborah A.
通讯作者：
Lannigan, Deborah A.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
--
作者：
Holm, Liisa;Kaariainen, Sakari;Plewczynski, Dariusz
通讯作者：
Plewczynski, Dariusz
影响因子：
3.2
作者：
Goettert, Marcia;Schattel, Verena;Laufer, Stefan
通讯作者：
Laufer, Stefan
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH