I-DOMAIN CONTAINING INTEGRIN/LIGAND INTERACTIONS

整合素/配体相互作用参与许多肿瘤的发病机制， 因此，它是治疗的目标。重大发现 在整联蛋白研究领域中， 包括：1）I结构域的晶体结构; 2）β-螺旋桨 α亚基N-末端的模型; 3）在α亚基中的I-结构域样结构， β亚基;和4）整联蛋白活化的模型。 我们 本项目期间的发现包括：1）配体结合 I结构域中的位点; 2）拟定β-螺旋桨结构域中的残基 3）决定配体结合的残基 β亚基的特异性;和4）多种构象依赖性 β亚基中的表位。 这些发现补充了晶体 结构的α-I域，并证实所提出的模型。 根据目前项目期间的进展情况，我们建议 研究：1）拟议的β-螺旋桨域在I 结构域/配体相互作用; 2）不同区域在 决定配体特异性的β 2亚基; 3）结合位点 β 2整合素中I-结构域中配体衍生的结合基序 整联蛋白;和4）阳离子结合在I结构域/配体中的作用 互动 拟议的研究将导致我们的 了解整合素的结构、调节和配体 交互. 这些研究可能会导致设计 可用于预防癌症的抑制剂或活化剂 转移、移植器官排斥或其他医学 条件

Integrin/ligand interaction is involved in the pathogenesis of many diseases and, therefore, is a therapeutic target. Significant findings in the field of integrin studies have been recently published, including: 1) The crystal structure of the I domain; 2) A Beta-propeller model of the alpha subunit N-terminus; 3) An I-domain-like structure in the Beta subunit; and 4) A model of integrin activation. Our discoveries during the current project period include: 1) Ligand binding sites in the I domain; 2) Residues in the proposed Beta-propeller domain that are critical for ligand binding; 3) Residues that determine ligand specificity in Beta subunits; and 4) multiple conformation-dependent epitopes in the Beta subunit. These findings complement the crystal structure of the alpha I domain, and substantiate the proposed models. Based on progress during the current project period, we propose to study: 1) the role of the proposed Beta-propeller domain in I domain/ligand interaction; 2) the role of the diverse region in the Beta2 subunit that determines ligand specificity; 3) the binding sites in Beta2 integrins for ligand-derived binding motifs in I-domain integrins; and 4) the role of cation binding in I domain/ligand interaction. The proposed studies will lead to an increase in our understanding of integrin structure, regulation, and ligand interactions. These studies could potentially lead to the design of inhibitors or activators that could be useful for preventing cancer metastasis, rejection of a transplanted organ, or other medical conditions.