TYK2 is a nonreceptor tyrosine kinase, member of the Janus kinases (JAK), with a central role in several diseases, including cancer. The JAKs' catalytic domains (KD) are highly conserved, yet the isolated TYK2-KD exhibits unique specificities. In a previous work, using molecular dynamics (MD) simulations of a catalytically impaired TYK2-KD variant (P1104A) we found that this amino acid change of its JAK-characteristic insert (αFG), acts at the dynamics level. Given that structural dynamics is key to the allosteric activation of protein kinases, in this study we applied a long-scale MD simulation and investigated an active TYK2-KD form in the presence of adenosine 5′-triphosphate and one magnesium ion that represents a dynamic and crucial step of the catalytic cycle, in other protein kinases. Community analysis of the MD trajectory shed light, for the first time, on the dynamic profile and dynamics-driven allosteric communications within the TYK2-KD during activation and revealed that αFG and amino acids P1104, P1105, and I1112 in particular, hold a pivotal role and act synergistically with a dynamically coupled communication network of amino acids serving intra-KD signaling for allosteric regulation of TYK2 activity. Corroborating our findings, most of the identified amino acids are associated with cancer-related missense/splice-site mutations of the Tyk2 gene. We propose that the conformational dynamics at this step of the catalytic cycle, coordinated by αFG, underlie TYK2-unique substrate recognition and account for its distinct specificity. In total, this work adds to knowledge towards an in-depth understanding of TYK2 activation and may be valuable towards a rational design of allosteric TYK2-specific inhibitors.

中文翻译：

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大规模分子动力学模拟的群落分析阐明了酪氨酸激酶 2 中动力学驱动的变构

TYK2 是一种非受体酪氨酸激酶，是 Janus 激酶 (JAK) 的成员，在包括癌症在内的多种疾病中发挥着核心作用。JAK 的催化结构域 (KD) 高度保守，但分离的 TYK2-KD 表现出独特的特异性。在之前的工作中，使用催化受损的 TYK2-KD 变体（P1104A）的分子动力学（MD）模拟，我们发现其 JAK 特征插入物（αFG）的这种氨基酸变化在动力学水平上起作用。鉴于结构动力学是蛋白激酶变构激活的关键，在这项研究中，我们应用了长期 MD 模拟，并研究了在 5'-三磷酸腺苷和一个代表动态的镁离子存在下的活性 TYK2-KD 形式。在其他蛋白激酶中也是催化循环的关键步骤。MD 轨迹的群体分析首次揭示了 TYK2-KD 激活过程中的动态概况和动态驱动的变构通讯，并揭示了 αFG 和氨基酸 P1104、P1105 和 I1112 尤其具有关键作用。作用并与动态耦合的氨基酸通讯网络协同作用，为 TYK2 活性的变构调节提供 KD 内信号传导。证实了我们的发现，大多数已识别的氨基酸与Tyk2基因的癌症相关错义/剪接位点突变有关。我们认为催化循环这一步的构象动力学由 αFG 协调，是 TYK2 独特底物识别的基础，并解释了其独特的特异性。总而言之，这项工作增加了对 TYK2 激活的深入了解，并且对于合理设计 TYK2 特异性抑制剂的变构可能有价值。