Community analysis of large-scale molecular dynamics simulations elucidated dynamics-driven allostery in tyrosine kinase 2.

IF 3.2 4区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Proteins-Structure Function and Bioinformatics Pub Date : 2024-04-01 Epub Date: 2023-11-10 DOI:10.1002/prot.26631
Nastazia Lesgidou, Metaxia Vlassi
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Abstract

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.

大规模分子动力学模拟的群落分析阐明了酪氨酸激酶2中动力学驱动的异构体。
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起着核心作用。JAKs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。在之前的一项工作中,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,在本研究中,我们应用了长期MD模拟,并研究了在其他蛋白激酶中,在5’-三磷酸腺苷和一种镁离子存在下的活性TYK2-KD形式,该镁离子代表催化循环的动态和关键步骤。MD轨迹的群落分析首次揭示了激活过程中TYK2-KD内的动力学特征和动力学驱动的变构通讯,并揭示了αFG和氨基酸P1104、P1105和I1112,发挥关键作用,并与为TYK2活性的变构调节提供KD内信号的氨基酸的动态耦合通信网络协同作用。证实了我们的发现,大多数已鉴定的氨基酸与Tyk2基因的癌症相关错义/剪接侧突变有关。我们提出,在催化循环的这一步,由αFG配位的构象动力学是TYK2独特底物识别的基础,并解释了其独特的特异性。总之,这项工作增加了对TYK2激活的深入理解,并可能对变构TYK2特异性抑制剂的合理设计有价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Proteins-Structure Function and Bioinformatics
Proteins-Structure Function and Bioinformatics 生物-生化与分子生物学
CiteScore
5.90
自引率
3.40%
发文量
172
审稿时长
3 months
期刊介绍: PROTEINS : Structure, Function, and Bioinformatics publishes original reports of significant experimental and analytic research in all areas of protein research: structure, function, computation, genetics, and design. The journal encourages reports that present new experimental or computational approaches for interpreting and understanding data from biophysical chemistry, structural studies of proteins and macromolecular assemblies, alterations of protein structure and function engineered through techniques of molecular biology and genetics, functional analyses under physiologic conditions, as well as the interactions of proteins with receptors, nucleic acids, or other specific ligands or substrates. Research in protein and peptide biochemistry directed toward synthesizing or characterizing molecules that simulate aspects of the activity of proteins, or that act as inhibitors of protein function, is also within the scope of PROTEINS. In addition to full-length reports, short communications (usually not more than 4 printed pages) and prediction reports are welcome. Reviews are typically by invitation; authors are encouraged to submit proposed topics for consideration.
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