Institute of Pharmaceutical Sciences, Research Group Pharmaceutical Bioinformatics, Albert-Ludwigs-University Freiburg, Hermann-Herder-Straße 9, 79104, Freiburg, Germany.
Sci Rep. 2018 Jun 21;8(1):9435. doi: 10.1038/s41598-018-27867-3.
In this work, we study the dynamics and the energetics of the all-atom structure of a neuronal-specific serine/threonine kinase c-Jun N-terminal kinase 3 (JNK3) in three states: unphosphorylated, phosphorylated, and ATP-bound phosphorylated. A series of 2 µs atomistic simulations followed by a conformational landscape mapping and a principal component analysis supports the mechanistic understanding of the JNK3 inactivation/activation process and also indicates key structural intermediates. Our analysis reveals that the unphosphorylated JNK3 undergoes the 'open-to-closed' movement via a two-step mechanism. Furthermore, the phosphorylation and ATP-binding allow the JNK3 kinase to attain a fully active conformation. JNK3 is a widely studied target for small-drugs used to treat a variety of neurological disorders. We believe that the mechanistic understanding of the large-conformational changes upon the activation of JNK3 will aid the development of novel targeted therapeutics.
在这项工作中，我们研究了神经元特异性丝氨酸/苏氨酸激酶 c-Jun N 末端激酶 3（JNK3）在三种状态下的全原子结构的动力学和能量学：未磷酸化、磷酸化和与 ATP 结合的磷酸化。一系列 2µs 的原子模拟，随后进行构象景观映射和主成分分析，支持了 JNK3 失活/激活过程的机制理解，并指出了关键的结构中间体。我们的分析表明，未磷酸化的 JNK3 通过两步机制经历“开-闭”运动。此外，磷酸化和 ATP 结合使 JNK3 激酶能够达到完全激活的构象。JNK3 是一种广泛研究的小分子药物靶点，用于治疗多种神经疾病。我们相信，对 JNK3 激活时的大构象变化的机制理解将有助于开发新的靶向治疗方法。
