BACKGROUND Helicobacter pylori is an important factor in the development of diseases such as ulcer and gastric cancer. This bacterium uses a periplasmic transporter, UreI, to deliver urea to the intracelullar space, where later it is transformed into ammonia by the cytoplasmic enzyme urease to survive the acidic condition of the human stomach. The UreI transporter presents a pH-dependent activity, where this pH-dependence remains unknown at a structural level. Althought the existance of several protonable residues in the periplasmic loops are related to the pH-dependent activity, we find interesting to have a clear view of the conformational changes involved in this phenomena through a molecular dynamic study. RESULTS Molecular dynamic simulations of the UreI transporter at three different pH conditions were performed, revealing two main pH-dependent conformations, which we present as the open and close states. We find that salt bridges between the periplasmic loops are crucial interactions that stabilize these conformations. Besides, a cooperative behaviour exists between the six subunits of the system that is necessary to fulfill the activity of this transporter. CONCLUSIONS We found different pH-dependent conformations of the urea transporter UreI from Helicobacter pylori, which are related to salt-bridge interactions in the periplasmic regions. The behaviour of every channel in the system is not independent, given the existance of a cooperative behaviour through the formation of salt-bridges between the subunits of the hexameric system. We believe that our results will be related to the generation of new eradication therapies using this transporter as an attractive target, denoting that the knowledge of the possible pH-dependent conformations adopted for this transporter are important for the development of rational drug design approximations.

中文翻译：

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周质环相互作用的变化决定了幽门螺杆菌的六聚尿素转运蛋白UreI的pH依赖性活性：一项分子动力学研究。

背景技术幽门螺杆菌是诸如溃疡和胃癌的疾病发展的重要因素。这种细菌利用周质转运蛋白UreI将尿素输送到细胞内腔，之后尿素被细胞质酶脲酶转化为氨，从而在人胃酸性条件下存活。UreI转运蛋白具有pH依赖性活性，在结构水平上这种pH依赖性仍然未知。尽管周质环中几个质子化残基的存在与pH依赖的活性有关，但我们发现通过分子动力学研究清楚了解这种现象所涉及的构象变化是很有趣的。结果在三种不同的pH条件下对UreI转运蛋白进行了分子动力学模拟，揭示了两个主要的pH依赖性构象，我们将其表示为开放状态和封闭状态。我们发现周质环之间的盐桥是稳定这些构象的关键相互作用。此外，系统的六个子单元之间存在协作行为，这是实现此转运蛋白活动所必需的。结论我们发现幽门螺杆菌的尿素转运蛋白UreI具有不同的pH依赖性构象，这与周质区的盐桥相互作用有关。给定存在通过六聚体系统的亚基之间的盐桥形成的协作行为，系统中每个通道的行为都不是独立的。