Structures of Alpha 4 Integrins, Ligands and Antagonists

Alpha 4 整合素、配体和拮抗剂的结构

• 批准号: 8607258
• 负责人: TIMOTHY A SPRINGER
• 金额: $ 38.39万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8607258
• 关键词: Structures; Alpha; Integrins; Ligands; Antagonists

Springer, Timothy A. Project 2 This project examines the specialized molecular features of integrins alpha4B7 and alpha4B1 and IgSF family members MAdCAM-1 and VCAM-1 that enable tethering, rolling, and firm adhesion of leukocytes on vascular endothelium in shear flow. The interaction between alpha4B1 and VCAM-1 is also important in development of the vasculature and the heart. The long-term goal is to acquire a deep understanding of adhesion in vascular flow, enhance treatment of vascular diseases including atherosclerosis, and accelerate development of therapeutics directed to alpha4 integrins. Four aims address these needs. 1. Structures of MAdCAM-1's integrin-binding loop in domain 1 will address a novel fold for domain 1, and the hypothesis that the unique flexibility of this loop relates to MAdCAM-1's unusual ability to support rolling adhesion through integrins, and that this loop adopts distinct conformations to support rolling and firm adhesion. 2. Crystal and EM structures will define the structure of the integrin alpha4B7 headpiece, how it binds to function blocking antibodies that are approved or in clinical trials to treat multiple sclerosis and inflammatory bowel disease, how small molecule antagonists bind, and the different conformational states adopted by the headpiece and ectodomain in EM. Structures reveal unique features of the ligand binding pocket at the interface between the alpha4 B-propeller and B7 I domains, unique metal-binding residues in B7, and how selectivity and affinity of small molecules can be further improved. 3. To examine how alpha4B7 and MAdCAM-1 can mediate both rolling and firm adhesion, we will obtain crystal structures demonstrating the distinct way in which MAdCAM-1, its peptides, and representative small molecule inhibitors, bind to the closed and open a4P7 headpiece conformations. Structures of MAdCAM-1 and/or MAdCAM-1-derived peptides complexed with the closed and open alpha4B7 headpieces will reveal how macromolecular ligands bind, and further test the hypothesis that the closed and open headpieces mediate low-affinity rolling and high-affinity firm adhesion, respectively. 4. Complex structures with the alpha4B1 headpiece will reveal how it binds to VCAM-1, fibronectin, and small molecule antagonists. Comparisons to alpha4B7 complexes will examine how an integrin B-subunit influences ligand specificity, functional correlates to rolling through alpha4B7 and alpha4B1and how differences between alpha4B17and alpha4B1 can be exploited to develop selective antagonists for the different diseases in which these integrins are important. Complexes with Fab relate function to alpha4B1 conformation.

蒂莫西·A·施普林格。项目2 该项目研究了整联蛋白alpha4b7和alpha4b1的专业分子特征以及IGSF家族成员MadCAM-1和VCAM-1，从而使白细胞在剪切流中的血管内皮上的白细胞固定，滚动和牢固的粘附。 alpha4b1和VCAM-1之间的相互作用在脉管系统和心脏的发展中也很重要。长期的目标是深入了解血管流中的粘附，增强包括动脉粥样硬化在内的血管疾病的治疗，并加速针对α4整合素的治疗剂。四个目标满足了这些需求。 1。域中MADCAM-1的整联蛋白结合环的结构将解决域1的新颖折叠，并且该循环的独特灵活性与MadCam-1的独特灵活性有关，与MadCam-1的不寻常能力相关，以支持通过整合素的滚动粘合剂的异常能力，并且该循环采用独特的构型来支撑滚动和牢固的粘附。 2。 晶体和EM结构将定义整联蛋白alpha4b7头饰的结构，它如何结合批准或临床试验中的功能阻断抗体，以治疗多发性硬化症和炎症性肠道疾病，小分子拮抗剂如何结合，以及由媒体和ectododice and ectododemain在EM中采用的不同构象状态。结构揭示了在alpha4 b螺旋桨和B7 I域之间的界面上配体结合袋，B7中独特的金属结合残基以及如何进一步改善小分子的选择性和亲和力。 3。要检查α4B7和MadCam-1如何介导滚动和牢固的粘附，我们将获得晶体结构，以证明MadCAM-1，其肽和代表性的小分子抑制剂的独特方式，与封闭的A4P7头型构型结合。 MADCAM-1和/或MADCAM-1衍生的肽与封闭和开放的alpha4b7头饰复合的结构将揭示大分子分子配体如何结合，并进一步检验封闭式和开放式头饰的假设分别介导了低亲和力的滚动和高亲和力的公司粘附。 4。带有alpha4b1头饰的复合结构将揭示其与VCAM-1，纤连蛋白和小分子拮抗剂的结合。与alpha4b7复合物的比较将检查整联蛋白B-亚基的影响配体特异性，功能与通过alpha4b7和alpha4b1的滚动如何相关，并且如何利用Alpha4b17和alpha4b1之间的差异来开发这些整合素很重要的不同疾病。具有FAB功能与alpha4b1构象相关的复合物。