HUMAN PLASMINOGEN: INTERACTIONS OF THE N-TERMINAL DOMAIN WITH KRINGLE MODULES,

人类纤溶酶原：N 末端结构域与 Kringle 模块的相互作用，

• 批准号: 7723270
• 负责人: MIGUEL LLINAS
• 金额: $ 0.05万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7723270
• 关键词: Affinity; Binding; Binding Sites; C-terminal; Computer Retrieval of Information on Scientific Projects Database; Docking; Enzyme Precursors; Free Energy; Funding; Grant; Human; Institution; Kringles; Ligand Binding; Lysine; Methods; Modeling; Molecular Conformation; Motion; N-terminal; Plasmin; Plasminogen; Play; Process; Protease Domain; Research; Research Personnel; Resources; Role; Source; United States National Institutes of Health; computer studies; insight; molecular dynamics

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Plasminogen, the proenzyme of plasmin, is ocmposed by an N-terminal module, five kringle repeats, and a C-terminal protease domain. We propose to study plasminogen's functional processes via molecular dynamics (MD) simulations. As an initial attempt to model and understand plasminogen action at the atomic level, we will perform a detailed MD study of each kringle repeat and investigate their N-terminus binding capability. The binding free energies between each kringle and the N-terminal domain will be computed and compared. We will focus primarily on lysine-binding sites, which are believed to play a central role in binding N-terminal. Nonetheless, docking methods will also be employed to conduct a broad search to identify their potential ligand binding sites. In addition, we will investigate relation between intrinsic conformational changes or vibrational motions and binding affinities using normal-mode analysis. The computational study proposed here will help to understand inter-domain interactions and binding processes and thus will provide important insight into the factors controlling the transition from a closed to an open conformation of plasminogen.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 纤溶酶原是纤溶酶的酶原，由 N 端模块、五个三环重复序列和 C 端蛋白酶结构域组成。我们建议通过分子动力学（MD）模拟来研究纤溶酶原的功能过程。作为在原子水平上模拟和理解纤溶酶原作用的初步尝试，我们将对每个 kringle 重复进行详细的 MD 研究，并研究它们的 N 末端结合能力。将计算并比较每个三环和 N 末端结构域之间的结合自由能。我们将主要关注赖氨酸结合位点，据信赖氨酸结合位点在 N 末端结合中发挥核心作用。尽管如此，对接方法也将用于进行广泛的搜索，以确定其潜在的配体结合位点。此外，我们将使用正态模式分析研究内在构象变化或振动运动与结合亲和力之间的关系。这里提出的计算研究将有助于理解域间相互作用和结合过程，从而为控制纤溶酶原从封闭构象到开放构象转变的因素提供重要的见解。