Contributions of Conformational Flexibility to High-Affinity Zinc Binding in the Solute Binding Protein AztC.
Contributions of Conformational Flexibility to High-Affinity Zinc Binding in the Solute Binding Protein AztC.
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DOI：
10.1021/acsomega.1c06639
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发表时间：
2022-02-01
期刊：
影响因子：
4.1
通讯作者：
Yukl ET
中科院分区：
文献类型：
--
作者：
Serrano FA;Yukl ET
细菌依靠ATP结合盒（ABC）转运蛋白输入各种营养物质。细菌ABC导入剂利用胞外溶质结合蛋白（SBP）以高亲和力和特异性结合底物，并将其递送至膜透性酶进行转运。必需金属铁、锰和锌通过簇A-I SBPs结合和运输。存在金属结合和无金属形式的几个簇A-I SBPs的晶体结构，其显示伴随金属结合的相对微妙的构象变化。最近的解决方案的研究和分子动力学模拟表明，一个更复杂的构象景观簇A-I SBPs，这表明在金属结合后的蛋白质动力学的变化可能有一个重要的作用，在识别膜透性酶和有效的运输。在这里，我们研究的构象状态和动力学簇A-I SBP AztC从Paracoccus spermficans，其不寻常的固有荧光行为和热力学锌结合。这些数据表明，至少有两个构象状态的载脂蛋白的形式和补偿性变化的全息提供了一个显着的熵贡献锌结合的动态平衡。与现有晶体结构的相关性表明，金属结合形式的Trp-Phe π-堆积相互作用的形成可能介导所观察到的荧光变化。这里确定的AztC的构象动力学可能适用于其他簇A-I SBP，与它们作为潜在抗生素药物靶标的开发有关。
Bacteria rely on ATP binding cassette (ABC) transporters for the import of various nutrients. Bacterial ABC importers utilize an extracellular solute binding protein (SBP) to bind the substrate with high affinity and specificity and deliver it to the membrane permease for transport. The essential metals iron, manganese, and zinc are bound and transported by the cluster A–I SBPs. Crystal structures exist for the metal-bound and metal-free forms of several cluster A–I SBPs that show relatively subtle conformational changes that accompany metal binding. Recent solution studies and molecular dynamics simulations indicate a more complex conformational landscape for the cluster A–I SBPs, suggesting that changes in protein dynamics upon metal binding may have an important role in recognition by the membrane permease and effective transport. Here, we investigate conformational states and dynamics in the cluster A–I SBP AztC fromParacoccus denitrificans, characterizing its unusual intrinsic fluorescence behavior and thermodynamics of zinc binding. These data suggest a dynamic equilibrium of at least two conformational states in the apo form and compensatory changes in the holo that provide for a significant entropic contribution to zinc binding. Correlation with available crystal structures suggests that the formation of a Trp–Phe π-stacking interaction in the metal-bound form may mediate the observed changes in fluorescence. The conformational dynamics identified here for AztC are likely applicable to other cluster A–I SBPs with relevance to their exploitation as potential antibiotic drug targets.
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