Structural basis of Jak3-mediated interleukin-2 family signal transduction

Jak3介导的白细胞介素2家族信号转导的结构基础

基本信息

批准号：
7431801
负责人：
Titus Jonathon Boggon
金额：
$ 40.58万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7431801
关键词：
Affinity Area Binding Biochemical Calorimetry Clinical Complex Cytokine Receptors Cytokine Signaling Cytoplasmic Tail Data Development Family Family member Goals Growth Healthcare Hematopoiesis Immune response Inflammation Interleukin 2 Receptor Gamma Interleukin-2 Janus kinase Laboratories Maintenance Malignant Neoplasms Mediating Methods Molecular Molecular Conformation Mutation Myeloproliferative disease Peptides Phosphotransferases Play Production Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Research Personnel Role Severe Combined Immunodeficiency Signal Pathway Signal Transduction Site-Directed Mutagenesis Specificity Structure Techniques Testing Therapeutic Therapeutic immunosuppression Titrations Tyrosine Kinase Inhibitor Work X-Ray Crystallography base cytokine design drug discovery ezrin immunoregulation improved inhibitor/antagonist leukemia programs radixin protein receptor small molecule structural biology

项目摘要

DESCRIPTION (provided by applicant): Proper function of cytokine signaling pathways is critical for immunoregulation, hematopoiesis, and cytokine- directed inflammation and growth. Most signals from type I and type II cytokines are mediated by the Janus kinase (Jak) family of non-receptor tyrosine kinases. Our plan is to discover the molecular basis for cytoplasmic signal transduction from the interleukin-2 family cytokines through Jak3. We will use structural biology to provide the first description of Jak interactions with cytokine receptor cytoplasmic tails, to investigate Jak kinase domain specificity, regulation and inhibition, and to describe the role of the PERM domain in kinase activation. Specifically, we will focus our work in three distinct areas. In Aim 1 we will determine crystal structures of the kinase domain of Jak3. Modulation of the immune response by suppression of Jak3 kinase activity has clinical precedence. We will determine the mode of binding for Jak3 tyrosine kinase inhibitors and aid the discovery of further inhibitors that may be useful as immunomodulatory and anti-proliferative therapies. We will also discover the mode of Jak3 binding to a Jak3-preferred substrate and discover the inactive conformation of the kinase. In Aim 2, we will determine the structural basis for the almost exclusive Jak3 association with the interleukin-2 receptor gamma subunit. For this we will solve crystal structures that describe the interaction of the Jak3 PERM domain with peptides from the interleukin-2 receptor gamma subunit and investigate their binding affinities. Finally, following our structural studies on the kinase and PERM domains of Jak3, in Aim 3 we will determine the structural basis for Jak3 kinase domain association with the Jak3 FERM domain. We will also test the role of this interface as a suggested Jak3 active state stabilizing mechanism. These studies will directly impact healthcare stimulating the development of improved immunomodulatory and anti-proliferative therapies and by enhancing molecular-level understanding of cytokine signaling pathways.

描述（由申请人提供）：细胞因子信号通路的适当功能对于免疫调节，造血和细胞因子定向炎症和生长至关重要。 I型和II型细胞因子的大多数信号都是由非受体酪氨酸激酶的Janus激酶（JAK）家族介导的。我们的计划是通过JAK3发现从白介素-2家族细胞因子的细胞质信号转导的分子基础。我们将使用结构生物学来提供与细胞因子受体细胞质尾部相互作用的首次描述，以研究JAK激酶结构域的特异性，调节和抑制，并描述PERS域在激酶激活中的作用。具体来说，我们将把工作集中在三个不同的领域。在AIM 1中，我们将确定JAK3激酶结构域的晶体结构。通过抑制JAK3激酶活性来调节免疫反应，具有临床优势。我们将确定JAK3酪氨酸激酶抑制剂结合的模式，并有助于发现可能作为免疫调节和抗增殖疗法有用的进一步抑制剂。我们还将发现JAK3结合与JAK3优先基质的模式，并发现激酶的无活性构象。在AIM 2中，我们将确定与白介素-2受体伽马亚基的几乎独家JAK3关联的结构基础。为此，我们将解决描述Jak3 pers域与白介素-2受体伽马亚基的肽相互作用并研究其结合亲和力的晶体结构。最后，遵循我们对JAK3激酶和PERS结构域的结构研究，在AIM 3中，我们将确定JAK3激酶结构域与JAK3 FERM结构域的结合的结构基础。我们还将测试该界面作为建议的JAK3主动状态稳定机制的作用。这些研究将直接影响刺激改善免疫调节和抗增殖疗法的发展，并通过增强对细胞因子信号通路的分子水平理解的发展。