Theoretical study of structure-function correlations of Aquaporin V and mutants

水通道蛋白V及其突变体结构-功能相关性的理论研究

• 批准号: 8708107
• 负责人: LIAO Y CHEN
• 金额: $ 11.03万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708107
• 关键词: AQP1 gene; Affinity; Antineoplastic Agents; Apoptosis; Binding; Biological Models; Biological Process; Body of pancreas; Cell Proliferation; Cell membrane; Cells; Chemicals; Colon; Computer Simulation; Disease; Drug Design; Duodenum; Environment; Event; Eye; Free Energy; Gases; Goals; High Performance Computing; Histidine; Human; Human body; In Vitro; Ions; Knowledge; Labyrinth; Lacrimal gland structure; Lead; Light; Lipid Binding; Lipids; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measures; Medicine; Methods; Modification; Molecular Conformation; Mutation; Pancreas; Permeability; Pharmaceutical Preparations; Phosphorylation; Physiological; Play; Proteins; Protomer; Research; Resolution; Role; Saline; Salivary Glands; Sampling; Signal Transduction; Site; Sjogren' s Syndrome; Solvents; Specificity; Stomach; Structure; Sweat Glands; System; Testing; Theoretical Studies; Time; Water; Woman; base; biological systems; computing resources; design; environmental change; innovation; mutant; overexpression; prevent; protein structure; protonation; public health relevance; research study; response; trafficking; water channel

DESCRIPTION (provided by applicant): Among the thirteen human aquaporins (AQP0-AQP12) distributed within cells of the stomach, duodenum, pancreas, airways, lungs, salivary glands, sweat glands, eyes, lacrimal glands, and the inner ear, AQP5 has been implicated in Sjogren's disease and in cancers of the lung, pancreas, colon etc.. Defective trafficking of AQP5 was found responsible for Sjogren's disease which inflicts about 4 million people (mostly women) in the US. Overexpression of AQP5 was identified in promoting cell proliferation and inhibiting apoptosis. Meanwhile, high-resolution x-ray structure of AQP5 has recently been determined. AQP5 resembles other aquaporins in its tetrameric conformation and in its water pore structure formed by each protomer. However, it lacks the four-fold quasi-symmetry among its four protomers and it contains a lipid, PS6, in its central pore. In light of the existent in vtro studies of AQP5's functions and its crystal structure, the following questions stand out: How does the structure of AQP5 embedded in the cell membrane under physiological conditions deviate from its crystallographic form? Does PS6 gate or inhibit the central pore? What are the specificities of the lipid-AQP5 interaction? How does the protein respond to its environmental changes in pH? And how does it respond to chemical modifications to its residues? These questions on the structure-function correlations of AQP5 need to be answered before new drugs can be designed that specifically target this protein. Answering these questions requires conducting extensive in silico experiments in an innovated approach. Two all-atom model systems of AQP5 embedded in a patch of lipid bi- layer explicitly solvated in physiological saline will be investigated: One with PS6 in the central pore of AQP5 and one without. Three specific aims will be pursued: 1.Determine the roles of the lipid in the central pore and identify the mechanism of its gating or inhibiting action. 2. Identify the protein's mechanisms of biological functions and determine its response to environmental changes. 3. Quantify AQP5's response to chemical modifications and thus identify the mechanisms of signaling, gating, or inhibiting its physiological functions. Upon completion of the proposed research, a detailed understanding will be achieved about AQP5's structure- function correlations: AQP5's degree of accessibility for trafficking before and after phosphorylation at the selected sites, the affinity and specificit of binding a lipid in its central pore, and the mechanisms of inhibiting and gating its physiological functions. The knowledge so gained will positively impact on finding new medicines to prevent and control AQP5-related diseases.

描述（由申请人提供）：在十三种人类水通道蛋白（AQP0-AQP12）中分布在胃，十二指肠，胰腺，气道，肺，肺部，唾液腺，汗腺，眼睛，眼睛，汗腺，泪腺，富集腺体以及内耳的呼吸中，AQP5与Sjogren at canjogren的pers pers cancp5有关发现AQP5的贩运有缺陷造成了Sjogren病，该疾病在美国造成了约400万人（主要是妇女）。在促进细胞增殖和抑制细胞凋亡时，发现了AQP5的过表达。 同时，最近已经确定了AQP5的高分辨率X射线结构。 AQP5类似于其四聚体构象中的其他水通道蛋白，并在每个杂种形成的水孔结构中类似于其水孔结构。然而，它在其四个原型中缺乏四倍的准对称性，并且在其中央孔中含有脂质PS6。鉴于对AQP5功能及其晶体结构的VTRO研究的存在，以下问题脱颖而出：在生理条件下，AQP5的结构如何嵌入细胞膜中？ PS6门还是抑制中心孔？脂质AQP5相互作用的特异性是什么？蛋白质如何应对其pH的环境变化？它如何应对化学修饰对其残基的修饰？在设计新药物以专门针对该蛋白质的新药之前，需要回答有关AQP5结构功能相关性的这些问题。回答这些问题需要以创新的方法进行大量的计算机实验。将研究在生理盐水中明确溶剂化的脂质双层中嵌入的AQP5的两个全原子模型系统：一个在AQP5的中央孔中带有PS6，一个没有PS6。将追求三个具体目标：1。确定脂质在中心孔中的作用，并确定其门控或抑制作用的机制。 2。确定蛋白质的生物学功能机制，并确定其对环境变化的反应。 3。量化AQP5对化学修饰的反应，从而确定信号传导，门控或抑制其生理功能的机制。拟议的研究完成后，将对AQP5的结构 - 功能相关性获得详细的理解：AQP5在所选地点的磷酸化之前和之后的贩运程度，在其中心孔隙中结合脂质的亲和力和特定的脂质的亲和力和具体性，以及抑制和抑制其生理功能的机制。如此获得的知识将对寻找新药物预防和控制与AQP5相关的疾病的新药物产生积极影响。