CRYSTAL STRUCUTURE STUDIES OF OCRL

OCRL的晶体结构研究

• 批准号: 8363538
• 负责人: Yuxin Mao
• 金额: $ 0.9万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363538
• 关键词: American Society of Hematology; C-terminal; Disease; Fanconi Syndrome; Funding; Grant; Kidney; Link; Mental Retardation; Molecular; N-terminal; National Center for Research Resources; Oculocerebrorenal Syndrome; PH Domain; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Side; Source; Structure; Tertiary Protein Structure; United States National Institutes of Health; congenital cataract; cost; enzyme mechanism; human disease; inositol-1,4,5-trisphosphate 5-phosphatase; insight; mutant; phosphoinositide-3,4,5-triphosphate

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. OCRL was originally identified as the product of the gene responsible for the OculoCerebroRenal syndrome of Lowe. The Lowe syndrome is an X-linked disorder involving congenital cataracts, mental retardation, and renal Fanconi syndrome. OCRL is a multi-domain protein comprising a central inositol 5-phosphatase domain that favours PI(4,5)P2 and PI(3,4,5)P3 as substrates. This domain is flanked at its C-terminal side by an ASH and a catalytically inactive RhoGAP-like domain and an N-terminal PH domain. We recently determined the x-ray structure of the termimal ASH and RhoGAP tandem domains and the NMR structure of the N-terminal PH domian. We are now aimed to determine the structure of OCRL mutants that related to human disease. We have obtained crystals of severl mutants. We expect by determination of the structure of OCRL mutants, we will gain insights on the molecular mechanism of this enzyme.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 OCRL 最初被鉴定为导致 Lowe 眼脑肾综合征的基因的产物。 Lowe 综合征是一种 X 连锁疾病，涉及先天性白内障、智力低下和肾范科尼综合征。 OCRL 是一种多结构域蛋白，包含中心肌醇 5-磷酸酶结构域，有利于 PI(4,5)P2 和 PI(3,4,5)P3 作为底物。该结构域的 C 端侧翼为 ASH 和催化失活的 RhoGAP 样结构域以及 N 端 PH 结构域。 我们最近确定了末端 ASH 和 RhoGAP 串联结构域的 X 射线结构以及 N 端 PH 结构域的 NMR 结构。我们现在的目标是确定与人类疾病相关的 OCRL 突变体的结构。我们已经获得了几种突变体的晶体。我们期望通过确定 OCRL 突变体的结构，我们将深入了解这种酶的分子机制。