Structural basis and biological consequences for JNK2/3 isoform selective aminopyrazoles.
Structural basis and biological consequences for JNK2/3 isoform selective aminopyrazoles.
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DOI：
10.1038/srep08047
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发表时间：
2015-01-27
影响因子：
4.6
通讯作者：
LoGrasso P
中科院分区：
文献类型：
--
作者：
Park H;Iqbal S;Hernandez P;Mora R;Zheng K;Feng Y;LoGrasso P
三种JNK亚型，JNK1， JNK2和JNK3已经被报道，并且每种亚型都具有独特的生物学功能。目前尚不清楚选择性抑制这些异构体是否会带来治疗或安全效益。为了探测JNK异构体的功能，我们设计了JNK2/3抑制剂，其选择性是JNK1的30倍。利用定点诱变和x射线晶体学，我们确定了JNK3中的L144是选择性的关键残基。为了测试JNK2/3选择性抑制剂是否能保护人类多巴胺能神经元免受神经毒素诱导的线粒体功能障碍，我们监测了活性氧（ROS）的产生和线粒体膜电位（MMP）。结果表明，JNK2/3选择性抑制剂对6-羟多巴胺诱导的ROS生成和MMP去极化具有保护作用。这些结果表明，开发JNK2/3选择性抑制剂是可能的，疏水口袋I中的残基负责选择性。此外，研究结果还表明，JNK2/3的抑制可能有助于保护线粒体功能并防止最终的细胞死亡。
Three JNK isoforms, JNK1, JNK2, and JNK3 have been reported and unique biological function has been ascribed to each. It is unknown if selective inhibition of these isoforms would confer therapeutic or safety benefit. To probe JNK isoform function we designed JNK2/3 inhibitors that have >30-fold selectivity over JNK1. Utilizing site-directed mutagenesis and x-ray crystallography we identified L144 in JNK3 as a key residue for selectivity. To test whether JNK2/3 selective inhibitors protect human dopaminergic neurons against neurotoxin-induced mitochondrial dysfunction, we monitored reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP). The results showed that JNK2/3 selective inhibitors protected against 6-hydroxydopamine-induced ROS generation and MMP depolarization. These results suggest that it was possible to develop JNK2/3 selective inhibitors and that residues in hydrophobic pocket I were responsible for selectivity. Moreover, the findings also suggest that inhibition of JNK2/3 likely contributed to protecting mitochondrial function and prevented ultimate cell death.
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影响因子：
6.1
作者：
Braithwaite SP;Schmid RS;He DN;Sung ML;Cho S;Resnick L;Monaghan MM;Hirst WD;Essrich C;Reinhart PH;Lo DC
通讯作者：
Lo DC
影响因子：
6.1
作者：
Fernandes, Kimberly A.;Harder, Jeffrey M.;Fornarola, Laura B.;Freeman, Robert S.;Clark, Abbot F.;Pang, Iok-Hou;John, Simon W. M.;Libby, Richard T.
通讯作者：
Libby, Richard T.
影响因子：
4
作者：
Feng, Yangbo;Chambers, Jeremy W.;Iqbal, Sarah;Koenig, Marcel;Park, HaJeung;Cherry, Lisa;Hernandez, Pamela;Figuera-Losada, Mariana;LoGrasso, Philip V.
通讯作者：
LoGrasso, Philip V.
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
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