Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200127, China.
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China.
Sci Rep. 2020 Aug 6;10(1):13276. doi: 10.1038/s41598-020-70381-8.
The zinc transcriptional regulator (ZitR) functions as a metalloregulator that fine tunes transcriptional regulation through zinc-dependent DNA binding. However, the molecular mechanism of zinc-driven allosteric control of the DNA binding to ZitR remains elusive. Here, we performed enhanced sampling accelerated molecular dynamics simulations to figure out the mechanism, revealing the role of protein dynamics in the zinc-induced allosteric control of DNA binding to ZitR. The results suggest that zinc-free ZitR samples distinct conformational states, only a handful of which are compatible with DNA binding. Remarkably, zinc binding reduces the conformational plasticity of the DNA-binding domain of ZitR, promoting the population shift in the ZitR conformational ensemble towards the DNA binding-competent conformation. Further co-binding of DNA to the zinc-ZitR complex stabilizes this competent conformation. These findings suggest that ZitR-DNA interactions are allosterically regulated in a zinc-mediated conformational preselection manner, highlighting the importance of conformational dynamics in the regulation of transcription factor family.
锌转录调节剂 (ZitR) 作为一种金属调节剂发挥作用，通过锌依赖性 DNA 结合精细调节转录调控。然而，锌驱动的 ZitR DNA 结合的别构控制的分子机制仍不清楚。在这里，我们进行了增强采样加速分子动力学模拟以找出该机制，揭示了蛋白质动力学在锌诱导的 ZitR DNA 结合的别构控制中的作用。结果表明，无锌 ZitR 会采样到不同的构象状态，只有少数几种状态与 DNA 结合兼容。值得注意的是，锌结合降低了 ZitR DNA 结合结构域的构象可塑性，促进了 ZitR 构象集合向 DNA 结合能力构象的种群转移。进一步将 DNA 与锌-ZitR 复合物共结合稳定了这种有能力的构象。这些发现表明，ZitR-DNA 相互作用是通过锌介导的构象预选择方式进行别构调节的，突出了构象动力学在转录因子家族调控中的重要性。
