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Ras, Cycling and Inhibition.

Ras，循环和抑制。

基本信息

批准号：
8311453
负责人：
Nicolas Nassar
金额：
$ 16.08万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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：
2007-05-04 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8311453
关键词：
Ras Cycling Inhibition.

项目摘要

DESCRIPTION (provided by applicant): GTP-binding proteins are key switches in signaling pathways that regulate critical cellular functions such as growth and differentiation. Ras, which serves as a prototype for GTP-binding is constitutively activated in a large number of cancers including those of the pancreas, bladder, colon, and lung. The long-term goal of this research is to interfere with the oncogenic forms of Ras in human disease by understanding its cycling. Because oncogenic Ras relies on its intrinsic ability to hydrolyze and exchange GTP, the primary goal of this research proposal is to better our understanding of Ras cycling between the active and inactive states by revealing structures of intermediates of the reactions of GTP hydrolysis and guanine nucleotide exchange. Screening of drugs that will stabilize a non-signaling conformation of oncogenic Ras will be also performed. This proposal is based on findings that altering the flexibility of a hinge region stabilizes structures of Ras that are normally transient. Using this approach, two structures of intermediates along the path for GTP hydrolysis were stabilized as well as an open non-signaling conformation, which is also adopted by the native protein. The first aim of this proposal tests the hypothesis that the open conformation of Ras mimics the structure of an intermediate for nucleotide exchange and the structu-e of an unappreciated native conformation. Additional structures of intermediates for Ras cycling will be generated by altering the flexibility of another hinge region. The generated mutants will be studied using a combination of structural, molecular dynamics, biochemical, and in vivo techniques. The second aim tests the hypothesis that Rho- family members and trimeric G-proteins do not follow the Ras path of GTP hydrolysis and nucleotide exchange despite strong sequence homology. The third aim uses biophysical, structural, and cellular approaches to study how small molecules identified by screening the NCI database interact with the open non-signaling conformation and inhibit oncogenic Ras in a pancreatic cancer model system. The outcome of the proposed research should improve our understanding of the regulation of key signaling proteins and our ability to interfere with their action in human diseases.

描述（由申请人提供）：GTP 结合蛋白是调节生长和分化等关键细胞功能的信号通路中的关键开关。 Ras 是 GTP 结合的原型，在多种癌症中被组成型激活，包括胰腺癌、膀胱癌、结肠癌和肺癌。这项研究的长期目标是通过了解 Ras 的循环来干扰人类疾病中的致癌形式。由于致癌 Ras 依赖于其水解和交换 GTP 的内在能力，因此本研究计划的主要目标是通过揭示 GTP 水解和鸟嘌呤核苷酸交换反应的中间体结构，更好地了解 Ras 在活性和非活性状态之间的循环。还将筛选能够稳定致癌 Ras 非信号构象的药物。该提议基于这样的发现：改变铰链区的灵活性可以稳定通常瞬态的 Ras 结构。使用这种方法，GTP 水解路径上的两种中间体结构以及开放的非信号构象得到了稳定，这也被天然蛋白质采用。该提案的第一个目的是测试 Ras 的开放构象模拟核苷酸交换中间体的结构和未受重视的天然构象的结构的假设。通过改变另一个铰链区的灵活性，可以生成 Ras 循环中间体的其他结构。将结合结构、分子动力学、生物化学和体内技术来研究产生的突变体。第二个目标测试以下假设：尽管具有很强的序列同源性，但 Rho 家族成员和三聚体 G 蛋白并不遵循 GTP 水解和核苷酸交换的 Ras 路径。第三个目标是利用生物物理、结构和细胞方法来研究通过筛选 NCI 数据库识别出的小分子如何与开放非信号构象相互作用并在胰腺癌模型系统中抑制致癌 Ras。拟议研究的结果应该提高我们对关键信号蛋白调节的理解以及我们干扰它们在人类疾病中的作用的能力。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The 1.35 A resolution structure of the phosphatase domain of the suppressor of T-cell receptor signaling protein in complex with sulfate.

T 细胞受体信号蛋白抑制因子与硫酸盐复合物的磷酸酶结构域的 1.35 A 解析结构。

DOI：
10.1107/s1744309110014259
发表时间：
2010
期刊：
Acta crystallographica. Section F, Structural biology and crystallization communications
影响因子：
0
作者：
Jakoncic,Jean;Sondgeroth,Benjamin;Carpino,Nick;Nassar,Nicolas
通讯作者：
Nassar,Nicolas

The Sts proteins target tyrosine phosphorylated, ubiquitinated proteins within TCR signaling pathways.