A dynamically coupled allosteric network underlies binding cooperativity in Src kinase.
A dynamically coupled allosteric network underlies binding cooperativity in Src kinase.
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DOI：
10.1038/ncomms6939
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发表时间：
2015-01-20
影响因子：
16.6
通讯作者：
Seeliger, Markus A.
中科院分区：
文献类型：
--
作者：
Foda, Zachariah H.;Shan, Yibing;Kim, Eric T.;Shaw, David E.;Seeliger, Markus A.
蛋白酪氨酸激酶是有吸引力的药物靶标，因为许多人类疾病与激酶活性的失调有关。然而，催化激酶结构域如何整合不同的信号并从活性构象转换为非活性构象仍不完全清楚。在这里，我们确定了一个变构网络的Src激酶的动态耦合的氨基酸连接到ATP和底物结合位点的调节位点。令人惊讶的是，反应物（ATP和肽底物）与Src激酶负协同结合，而产物（ADP和磷酸肽）与正协同结合。我们通过生物化学研究证实了通过变构网络的信号中继的分子细节。对另外两种蛋白酪氨酸激酶的实验表明，这些酶之间的变构网络可能在很大程度上是保守的。我们的工作为蛋白酪氨酸激酶的调节提供了新的见解，并建立了一个潜在的管道，通过该管道，对ATP竞争性激酶抑制剂的抗性突变可以影响其活性。 蛋白酪氨酸激酶受多种调节机制的影响。Foda等人表明，酪氨酸激酶Src的反应物和产物以相反的协同性结合其催化结构域，并确定了这种行为背后的动态偶联氨基酸的变构网络。
Protein tyrosine kinases are attractive drug targets because many human diseases are associated with the deregulation of kinase activity. However, how the catalytic kinase domain integrates different signals and switches from an active to an inactive conformation remains incompletely understood. Here we identify an allosteric network of dynamically coupled amino acids in Src kinase that connects regulatory sites to the ATP- and substrate-binding sites. Surprisingly, reactants (ATP and peptide substrates) bind with negative cooperativity to Src kinase while products (ADP and phosphopeptide) bind with positive cooperativity. We confirm the molecular details of the signal relay through the allosteric network by biochemical studies. Experiments on two additional protein tyrosine kinases indicate that the allosteric network may be largely conserved among these enzymes. Our work provides new insights into the regulation of protein tyrosine kinases and establishes a potential conduit by which resistance mutations to ATP-competitive kinase inhibitors can affect their activity. Protein tyrosine kinases are subject to multiple regulatory mechanisms. Foda et al. show that reactants and products of the tyrosine kinase Src bind its catalytic domain with opposite cooperativity, and identify an allosteric network of dynamically coupled amino acids that underlie this behaviour.
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