STRUCTURE FUNCTION RELATIONSHIPS OF ACTIVIN AND ITS RECEPTORS

激活素及其受体的结构功能关系

基本信息

批准号：
7416766
负责人：
WOLFGANG H FISCHER
金额：
$ 16.48万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
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/7416766
关键词：
Activin Receptor Activins Agonist Alanine Amino Acid Sequence Amino Acids Behavior Binding Binding Proteins Binding Sites Biological Biological Availability Bone Morphogenetic Proteins C-terminal Cell Surface Receptors Collaborations Complex Computer Simulation Data Development Embryonic Development Epitopes Event Exhibits Extracellular Domain Follicle Stimulating Hormone Follistatin Future Goals In Vitro Investigation Lead Ligand Binding Ligands Mediating Membrane Proteins Mesoderm Modeling Mutagenesis Mutate Mutation Nerve Cell Survival Osteogenesis Ovary Play Process Property Publishing Reagent Recruitment Activity Regulation Relative (related person)Reproduction Research Personnel Role Signal Transduction Site Site-Directed Mutagenesis Specificity Structure Structure-Activity Relationship Surface System Testing Testis Therapeutic Therapeutic Agents Type I Activin Receptors Type II Activin Receptors Wound Healing activin A analog base bone morphogenetic protein 2 bone morphogenetic protein 7 cell growth design extracellular genetic regulatory protein in vivo inhibin inhibitor/antagonist mutant neoplastic novel paralogous gene programs receptor receptor binding reproductive function response small molecule three dimensional structure

项目摘要

Activin plays a critical role in the regulation of reproduction. It also controls cell growth and differentiation in diverse processes such as mesoderm induction during embryogenesis, nerve cell survival, bone formation and wound repair. This Project proposes to characterize the binding surfaces on activin and its receptors. We will employ site-directed mutagenesis to generate ligand and receptor mutants with disrupted or altered binding properties. In addition, activin mutants that compete with the binding of wild-type activin to its receptors and/or follistatin will be developed and tested for their effects on the bioavailability of endogenous activin. The structure of Bone Morphogenetic Protein 2 (BMP-2) bound to its type IA receptor soluble extracellular domain (BRIA-ECD) has been published and Project II of this Program has recently solved the structure of BMP-7 in complex with the activin type II receptor extracellular domain (ActRII-ECD). These crystal structures will enable the use of amino acid sequence comparisons and computer modeling approaches to predict residues critical for activin:receptor binding. Defining the residues constituting the binding interfaces between activin and its receptors will allow rational design of bioactive activin analogs and small molecule activin agonists or antagonists. These reagents will have therapeutic potential based on their ability to mimic or block activin actions including its effects on reproductive function.

激活素在调节繁殖中起关键作用。它还控制细胞生长和分化在胚胎发生，神经细胞存活，骨形成和伤口修复过程中中胚层诱导等多种过程中的分化。该项目建议表征激活素及其受体上的结合表面。我们将采用定向定向的诱变来产生具有破坏或改变结合特性的配体和受体突变体。此外，将开发并测试与野生型激活素与其受体和/或卵泡蛋白结合的结合的激活素突变体对内源性激活素的生物利用度的影响进行开发和测试。骨形态发生蛋白2（BMP-2）的结构与IA型受体可溶细胞外结合域（BRIA-ECD）已发表，该程序的项目II最近解决了BMP-7与激活素II型受体细胞外结构域（ACTRII-ECD）中复杂的结构。这些晶体结构将能够使用氨基酸序列比较和计算机建模方法来预测对激活素至关重要的残基：受体结合。定义构成激活素及其受体之间结合界面的残基将允许生物活性激活素类似物和小分子激活素激动剂或拮抗剂的合理设计。这些试剂将根据其模仿或阻断激活素作用的能力，包括其对生殖功能的影响，具有治疗潜力。