STRUCTURAL STUDIES OF INTEGRIN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 整合素是一个跨膜受体家族，调节细胞迁移、分化、程序性细胞死亡和细胞黏附。具体地说，人类整合素α-11-β-3调节血小板聚集，这可能导致动脉粥样硬化斑块破裂后冠状动脉中血栓的形成，最终导致心肌梗死。整合素分子的各种功能是由细胞外黏附分子与细胞内环境之间的动态联系控制的，而细胞外配体和分子与细胞质结构域结合而产生的跨膜信号又反过来调节着细胞外黏附分子与细胞内环境之间的动态联系。耶格尔博士的实验室以前曾利用电子冷冻显微镜确定低亲和力、非活性构象中的全长α-11-β-3的结构，这与X射线结晶学研究一起，为整合素激活相关的结构重排提出了一个模型。我们希望通过利用电子冷冻显微镜来测试这一模型，以提高低亲和力状态下α-11-β-3的3D重建的分辨率，并在结合配体存在的情况下生成高亲和力状态的3D图。这些研究将为整合素激活的分子基础提供重要的洞察力，这将与新型治疗剂的设计相关。

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. Integrins are a family of transmembrane receptors that regulate cell migration, differentiation, programmed cell death, and cell adhesion. Specifically, the human integrin alpha-11-beta-3 regulates platelet aggregation, which can lead to thrombus formation in a coronary artery following the rupture of an atherosclerotic plaque and ultimately myocardial infarction. The various functions of integrin molecules are controlled by dynamic linkages between extracellular adhesion molecules and the intracellular environment, which are in turn regulated by transmembrane signaling resulting from the binding of extracellular ligands and molecules to the cytoplasmic domain. Dr. Yeager's laboratory has previously utilized electron cryo-microscopy to determine the structure of full-length alpha-11-beta-3 in the low-affinity, inactive conformation, which along with X-ray crystallographic studies enabled a model to be proposed for the structural rearrangements associated with integrin activation. We wish to test this model by utilizing electron cryo-microscopy to improve the resolution of the 3D reconstruction of alpha-11-beta-3 in the low-affinity state and to generate a 3D map of the high-affinity state in the presence of bound ligands. These studies should provide crucial insight into the molecular basis of integrin activation, which will be relevant for the design of novel therapeutic agents.