STRUCTURAL STUDIES OF INTEGRIN

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。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粘附。具体而言，人整联蛋白α-11-β-3调节血小板聚集，这可导致动脉粥样硬化斑块破裂后冠状动脉中的血栓形成并最终导致心肌梗死。整合素分子的各种功能由细胞外粘附分子和细胞内环境之间的动态连接控制，细胞外粘附分子和细胞内环境又由细胞外配体和分子与细胞质结构域结合产生的跨膜信号传导调节。耶格尔博士的实验室以前已经利用电子冷冻显微镜来确定全长α-11-β-3在低亲和力、非活性构象中的结构，这沿着X射线晶体学研究使得能够提出与整合素活化相关的结构重排模型。我们希望通过利用电子冷冻显微镜来测试该模型，以提高低亲和力状态下α-11-β-3的3D重建的分辨率，并在结合配体的存在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见解，这将与新型治疗药物的设计相关。

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.