Crystal Structures of the p21-activated kinases PAK4, PAK5, and PAK6 reveal catalytic domain plasticity of active group II PAKs.
Crystal Structures of the p21-activated kinases PAK4, PAK5, and PAK6 reveal catalytic domain plasticity of active group II PAKs.
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DOI：
10.1016/j.str.2007.01.001
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发表时间：
2007-02
期刊：
影响因子：
5.7
通讯作者：
Knapp, Stefan
中科院分区：
文献类型：
--
作者：
Eswaran, Jeyanthy;Lee, Wen Hwa;Debreczeni, Judit E.;Filippakopoulos, Panagis;Turnbull, Andrew;Fedorov, Oleg;Deacon, Sean W.;Peterson, Jeffrey R.;Knapp, Stefan
p21活化激酶根据其结构域结构可分为两类。II组PAKs （PAK4-6）调节多种细胞功能，PAK失调与肿瘤发展有关。五种高分辨率结构的结构比较，包括所有活性的，单磷酸化的II族催化结构域，揭示了令人惊讶的结构域可塑性程度，包括一些催化生产性和非生产性构象。螺旋αC（激酶功能的关键调节元件）的重排导致αC N端额外的螺旋旋转和C端扭曲，这是迄今为止在蛋白激酶中未见的运动。观察到的结构变化导致保守残基之间形成相互作用，这些相互作用在结构上连接了富含甘氨酸的环αC和激活段，并将αC牢固地固定在一个活性构象中。抑制剂筛选鉴定出6种有效的PAK抑制剂，其中一种三取代嘌呤抑制剂与PAK4和PAK5共结晶。
p21-activated kinases have been classified into two groups based on their domain architecture. Group II PAKs (PAK4–6) regulate a wide variety of cellular functions, and PAK deregulation has been linked to tumor development. Structural comparison of five high-resolution structures comprising all active, monophosphorylated group II catalytic domains revealed a surprising degree of domain plasticity, including a number of catalytically productive and nonproductive conformers. Rearrangements of helix αC, a key regulatory element of kinase function, resulted in an additional helical turn at the αC N terminus and a distortion of its C terminus, a movement hitherto unseen in protein kinases. The observed structural changes led to the formation of interactions between conserved residues that structurally link the glycine-rich loop, αC, and the activation segment and firmly anchor αC in an active conformation. Inhibitor screening identified six potent PAK inhibitors from which a tri-substituted purine inhibitor was cocrystallized with PAK4 and PAK5.
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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：
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影响因子：
11.4
作者：
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DOI：
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1999-01-01
期刊：
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影响因子：
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作者：
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通讯作者：
Favaudon, V
影响因子：
11.4
作者：
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影响因子：
2.9
作者：
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