METALLOPROTEASE DOCKED WITH TIMP--ANGIOGENESIS INHIBITOR

描述（来自应用程序）： 类风湿性关节炎和其他疾病的进展取决于 血管生成 血管生成由蛋白水解级联介导， 基质金属蛋白酶（MMP）。 金属蛋白酶的组织抑制剂 （TIMPs）抑制血管生成。 模拟TIMP的抑制剂， MMP依赖性血管生成，但更容易制备和递送， 选择性地抑制基质金属蛋白酶的关键成员， 家庭将成为治疗类风湿性关节炎和其他疾病的有效药物。 血管生成性疾病 长期的TIMP模拟研究需要了解 TIMP/MMP复合物的三维结构。 最近的研究结果提出了关于TIMP/MMP的性质的假设， 界面，需要进一步评估：复合物的高亲和力 可以解释为多个接触，比那些小的更广泛 MMPs的分子抑制剂。 这些接触中的许多可以是疏水性的。 TIMP可以呈现与MMP的S形金属结合环的接触。 具体的目标涉及对接人MMP-3的NMR结构和人MMP-2的NMR结构。 使用NMR光谱法测定人TIMP-1的抑制结构域。 本初步 复杂的3D模型将适合于评估以下假设： 接口的特性。 核磁共振结构对接步骤 需要鉴别以下化合物的脂族H（1）和C（13）峰位置 每种蛋白质和分子间NOE光谱的解释， 反映了金属蛋白酶与TIMP之间的密切联系。 TIMP/MMP复合物的三维结构和对TIMP/MMP复合物的观察 其界面的特性将作为一个模板， 努力开发一种微型TIMP或其他TIMP模拟剂，以抑制 血管生成

DESCRIPTION (from the application): Progression of rheumatoid arthritis and other diseases depends upon angiogenesis. Angiogenesis is mediated by a proteolytic cascade involving matrix metalloproteinases (MMPs). Tissue Inhibitors of Metalloproteinases (TIMPs) suppress angiogenesis. Agents which mimic TIMP in inhibition of MMP-dependent angiogenesis but which are easier to prepare and deliver or which selectively inactivate key members of the matrix metalloproteinase family would make powerful therapeuticals for rheumatoid arthritis and other angiogenic diseases. Long-term efforts in mimicry of TIMP require knowing the three-dimensional structure of a TIMP/MMP complex. Recent results suggest hypotheses about the nature of the TIMP/MMP interface, requiring further evaluation: The high affinity of the complex may be explained by multiple contacts, more extensive than those of small molecule inhibitors of MMPs. Many of these contacts may be hydrophobic. TIMP may present contacts to the S-shaped, metal-binding loop of the MMP. The specific aims involve docking the NMR structures of human MMP-3 and the inhibitory domain of human TIMP-l, using NMR spectroscopy. This preliminary 3D model of the complex will be suitable for evaluating the hypotheses about the character of the interface. The steps to docking the structures by NMR require identification of the aliphatic H(1) and C(13) peak positions of each protein and interpretation of the intermolecular NOE spectra, reflecting the close contacts between metalloprotease and TIMP. Three-dimensional structure of the TIMP/MMP complex and insight into the character of its interface will serve as a template to stimulate long-range efforts to develop a mini-TIMP or other TIMP-mimicking agents to stifle angiogenesis.