Comparative analyses of lipoprotein lipase, hepatic lipase, and endothelial lipase, and their binding properties with known inhibitors.
Comparative analyses of lipoprotein lipase, hepatic lipase, and endothelial lipase, and their binding properties with known inhibitors.
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DOI：
10.1371/journal.pone.0072146
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Wang Z;Li S;Sun L;Fan J;Liu Z
甘油三酯脂肪酶基因亚家族在脂质和脂蛋白代谢中起着核心作用。该亚家族有三个成员：脂蛋白脂肪酶、肝脂肪酶和内皮脂肪酶。虽然这些脂肪酶与高脂血症和动脉粥样硬化的病理生理学有关，但它们的结构尚未完全清楚。本研究建立了这三种脂肪酶的同源模型，并对其活性位点进行了分析。此外，我们研究了催化残留物的动力学特性，使用分子动力学模拟策略。为了阐明分子间的相互作用，并确定潜在的关键残基参与脂肪酶抑制剂的结合，我们分析了结合口袋和已知的三种脂肪酶抑制剂的结合姿势。我们确定了空间一致催化三联体“Ser-Asp-His”，这是所有三种脂肪酶的特征基序。此外，我们发现脂肪酶分子的结合口袋的空间特征在配体识别、结合位姿和亲和力中起着关键作用。据我们所知，这是第一个报告，系统地建立了所有的甘油三酯脂肪酶基因亚家族成员的同源性模型。我们的数据提供了新的见解，脂肪酶的分子结构和它们的结构与功能的关系，从而为功能探针的设计提供了基础，对脂肪酶为基础的治疗性抑制剂治疗高脂血症和动脉粥样硬化。
The triglyceride lipase gene subfamily plays a central role in lipid and lipoprotein metabolism. There are three members of this subfamily: lipoprotein lipase, hepatic lipase, and endothelial lipase. Although these lipases are implicated in the pathophysiology of hyperlipidemia and atherosclerosis, their structures have not been fully solved. In the current study, we established homology models of these three lipases, and carried out analysis of their activity sites. In addition, we investigated the kinetic characteristics for the catalytic residues using a molecular dynamics simulation strategy. To elucidate the molecular interactions and determine potential key residues involved in the binding to lipase inhibitors, we analyzed the binding pockets and binding poses of known inhibitors of the three lipases. We identified the spatial consensus catalytic triad “Ser-Asp-His”, a characteristic motif in all three lipases. Furthermore, we found that the spatial characteristics of the binding pockets of the lipase molecules play a key role in ligand recognition, binding poses, and affinities. To the best of our knowledge, this is the first report that systematically builds homology models of all the triglyceride lipase gene subfamily members. Our data provide novel insights into the molecular structures of lipases and their structure-function relationship, and thus provides groundwork for functional probe design towards lipase-based therapeutic inhibitors for the treatment of hyperlipidemia and atherosclerosis.
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