STRUCTURAL STUDIES OF INTEGRIN

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。整合素是一类跨膜受体，可调节细胞迁移、分化、程序性细胞死亡和细胞粘附。具体来说，人整合素α -11- β -3调节血小板聚集，血小板聚集可导致动脉粥样硬化斑块破裂后冠状动脉血栓形成，最终导致心肌梗死。整合素分子的各种功能是由细胞外粘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的结合又通过跨膜信号传导来调节。Yeager博士的实验室以前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，这与x射线晶体学研究一起，使与整合素激活相关的结构重排模型得以提出。我们希望利用电子冷冻显微镜对该模型进行测试，以提高α -11- β -3在低亲和力状态下的三维重建分辨率，并在结合配体存在的情况下生成高亲和力状态的三维图。这些研究将为整合素激活的分子基础提供重要的见解，这将与新型治疗剂的设计有关。

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.