Variations in periplasmic loop interactions determine the pH-dependent activity of the hexameric urea transporter UreI from Helicobacter pylori: a molecular dynamics study.
Variations in periplasmic loop interactions determine the pH-dependent activity of the hexameric urea transporter UreI from Helicobacter pylori: a molecular dynamics study.
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周质环相互作用的变化决定了幽门螺杆菌中六聚体尿素转运蛋白UREI的pH依赖性活性：一项分子动力学研究。
DOI：
10.1186/s12900-015-0038-0
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发表时间：
2015-06-26
影响因子：
--
通讯作者：
Salas-Burgos A
中科院分区：
文献类型：
--
作者：
Cáceres-Delpiano J;Teneb J;Mansilla R;García A;Salas-Burgos A
幽门螺杆菌是引起胃溃疡、胃癌等疾病的重要因素。这种细菌使用周质转运蛋白UreI将尿素递送到细胞内空间，随后通过细胞质酶尿素酶将其转化为氨，以在人类胃的酸性条件下存活。UreI转运蛋白呈现pH依赖性活性，其中这种pH依赖性在结构水平上仍然未知。虽然在周质环中存在的几个可质子化的残基与pH依赖的活性有关，但我们发现有趣的是通过分子动力学研究清楚地了解这一现象所涉及的构象变化。分子动力学模拟的UreI转运蛋白在三个不同的pH值条件下进行，揭示了两个主要的pH值依赖的构象，我们目前作为开放和关闭状态。我们发现，盐桥之间的周质环是至关重要的相互作用，稳定这些构象。此外，该系统的六个亚单位之间存在合作行为，这是实现该转运蛋白活性所必需的。我们发现不同的pH值依赖的构象尿素转运蛋白UreI从幽门螺杆菌，这是相关的盐桥相互作用的周质区域。系统中每个通道的行为不是独立的，因为存在通过在六聚体系统的亚基之间形成盐桥的合作行为。我们相信，我们的研究结果将涉及到新的根除疗法的产生，使用这种转运蛋白作为一个有吸引力的目标，这意味着知识的可能的pH依赖性构象通过这种转运蛋白是重要的合理的药物设计近似的发展。本文的在线版本（doi：10.1186/s12900-015-0038-0）包含补充材料，可供授权用户使用。
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. 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. 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. The online version of this article (doi:10.1186/s12900-015-0038-0) contains supplementary material, which is available to authorized users.
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影响因子：
16.6
作者：
McNulty, Reginald;Ulmschneider, Jakob P.;Luecke, Hartmut;Ulmschneider, Martin B.
通讯作者：
Ulmschneider, Martin B.
DOI：
10.1073/pnas.93.25.14648
发表时间：
1996-12-10
影响因子：
11.1
作者：
Censini, S;Lange, C;Covacci, A
通讯作者：
Covacci, A
影响因子：
3.1
作者：
HU, LT;MOBLEY, HLT
通讯作者：
MOBLEY, HLT
影响因子：
3.2
作者：
CUSSAC, V;FERRERO, RL;LABIGNE, A
通讯作者：
LABIGNE, A
影响因子：
4.8
作者：
Weeks, DL;Gushansky, G;Sachs, G
通讯作者：
Sachs, G