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。血管生成是由蛋白水解级联反应介导的 基质金属蛋白酶(MMPs)。金属蛋白酶的组织抑制物 (TIMPs)抑制血管生成。模拟TIMP的药物对细胞生长的抑制作用 依赖于基质金属蛋白酶的血管生成，但更容易制备和传递或 选择性地灭活基质金属蛋白酶的关键成员 家族将为类风湿性关节炎和其他疾病制造强大的治疗药物 血管新生疾病。模仿TIMP的长期努力需要知道 TIMP/MMP复合体的三维结构。 最近的研究结果提示关于TIMP/MMPs的性质的假说 界面，需要进一步评估：复合体的高亲和力 可能由多个联系人解释，比小范围的联系人更广泛 MMPs的分子抑制剂。这些接触中的许多可能是疏水性的。 TIMP可能与基质金属膜的S形金属结合环有接触。 具体目标包括对接人基质金属蛋白酶-3的核磁共振结构和 人TIMP-L抑制结构域的核磁共振波谱分析。这是初步的 该复合体的3D模型将适用于评估关于 界面的特征。核磁共振对接结构的步骤 要求确定脂肪族H(1)和C(13)的峰位置 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/基质金属蛋白酶复合体的三维结构及对其影响的研究 它的界面特征将作为远程刺激的模板 努力开发迷你TIMP或其他模拟TIMP的试剂以扼杀 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.