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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Role of sequence evolution and conformational dynamics in the substrate specificity and oligomerization mode of thymidylate kinases
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Role of sequence evolution and conformational dynamics in the substrate specificity and oligomerization mode of thymidylate kinases

机译：序列演化和构象动态在胸苷激酶的底物特异性和低聚模式中的作用

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摘要

Thymidylate kinase (TMK) is a key enzyme for the synthesis of DNA, making it an important target for the development of anticancer, antibacterial, and antiparasitic drugs. TMK homologs exhibit significant variations in sequence, residue conformation, substrate specificity, and oligomerization mode. However, the influence of sequence evolution and conformational dynamics on its quaternary structure and function has not been studied before. Based on extensive sequence and structure analyses, our study detected several non-conserved residues which are linked by co-evolution and are implicated in the observed variations in flexibility, oligomeric assembly, and substrate specificity among the homologs. These lead to differences in the pattern of interactions at the active site in TMKs of different specificity. The method was further tested on TMK from Sulfolobus tokodaii (StTMK) which has substantial differences in sequence and structure compared to other TMKs. Our analyses pointed to a more flexible dTMP-binding site in StTMK compared to the other homologs. Binding assays proved that the protein can accommodate both purine and pyrimidine nucleotides at the dTMP binding site with comparable affinity. Additionally, the residues responsible for the narrow specificity of Brugia malayi TMK, whose three-dimensional structure is unavailable, were detected. Our study provides a residue-level understanding of the differences observed among TMK homologs in previous experiments. It also illustrates the correlation among sequence evolution, conformational dynamics, oligomerization mode, and substrate recognition in TMKs and detects co-evolving residues that affect binding, which should be taken into account while designing novel inhibitors.
机译：胸苷酸酯激酶（TMK）是用于合成DNA的关键酶，使其成为抗癌，抗菌和抗贫磷脂的发展的重要靶标。 TMK同源物表现出序列，残留物构象，底物特异性和寡聚化模式的显着变化。然而，之前尚未研究序列演化和构象动态对其第四纪结构和功能的影响。基于广泛的序列和结构分析，我们的研究检测了几种由共进进化连接的非保守残基，并且涉及在同源物中观察到的柔韧性，低聚组件和底物特异性的变化。这些导致在不同特异性的TMKS中活性位点的相互作用模式的差异。该方法进一步测试了来自苏尔鼠Tokodaii（STTMK）的TMK，与其他TMK相比，序列和结构具有大量差异。我们的分析指向STTMK中更灵活的DTMP结合位点与其他同源物相比。结合测定证明，蛋白质可以在DTMP结合位点处容纳嘌呤和嘧啶核苷酸，其具有可比亲和力。另外，检测到兔子Malayi TMK狭窄特异性的残基，其三维结构不可用。我们的研究提供了对先前实验中TMK同源物中观察到的差异的残留水平。它还说明了TMK中序列演化，构象动态，寡聚化模式和底物识别的相关性，并检测影响结合的共同不断的残基，这在设计新抑制剂的同时应考虑。

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