HSP90 CONFORMATIONAL REQUIREMENTS FOR KINASE MATURATION

HSP90 激酶成熟的构象要求

• 批准号: 8168638
• 负责人: DANIEL N BOLON
• 金额: $ 0.54万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168638
• 关键词: Binding; Biology; C-terminal; Computer Retrieval of Information on Scientific Projects Database; Data; Engineering; Eukaryota; Funding; Grant; Institution; Medicine; Modeling; Molecular; Molecular Chaperones; Molecular Conformation; N Domain; N-terminal; Oncogenic; Phosphotransferases; Process; Research; Research Personnel; Resources; Roentgen Rays; Source; Structure; United States National Institutes of Health; anti-cancer therapeutic; design; dimer; in vivo; inhibitor/antagonist; insight; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hsp90 is an essential chaperone in eukaryotes that is involved in the maturation of numerous kinases. Because numerous oncogenic kinases rely on Hsp90 for their function, Hsp90 has emerged as a promising target for anti-cancer therapeutics. The design of effective Hsp90 inhibitors would benefit from a molecular understanding of Hsp90 mechanism. Recently, two structures of Hsp90 have been determined both with the C-terminal domain forming a stable dimer. In one structure the N-terminal domain is also dimerized forming a closed state, and in the other structure the N-terminal domain is separated by a large distance (>60 Angstroms). Small-angle X-ray scattering (SAXS) experiments are consistent with a model where ATP-binding shifts Hsp90 from the open to the closed conformation. To determine if the open conformation is involved in kinase maturation, we have engineered Hsp90 with a coiled-coil to hold the N-domain in the closed conformation in the absence of ATP binding. SAXS experiments at APS would provide critical data to determine the conformational states of our engineered Hsp90 molecules both in the presence and absence of ATP. Combined with in vivo studies currently underway to analyze kinase maturation, the SAXS data will provide important insights into a fundamental process in biology and medicine.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 HSP90是真核生物中必不可少的伴侣，它参与了许多激酶的成熟。由于许多致癌激酶依赖于HSP90来发挥其功能，因此HSP90已成为抗癌治疗的有希望的靶标。有效HSP90抑制剂的设计将受益于对HSP90机制的分子理解。最近，HSP90的两个结构都通过C末端结构域形成稳定的二聚体确定。在一个结构中，N末端结构域也二聚体形成封闭状态，在另一个结构中，N末端结构域被大距离（> 60埃埃斯特罗姆）隔开。小角度X射线散射（SAXS）实验与ATP结合的模型一致，其中ATP结合将HSP90从开放式转移到封闭构象。为了确定激酶成熟中是否涉及开放构象，我们已经用盘绕的螺旋线设计了HSP90，以在没有ATP结合的情况下将N域的n-domain保持在闭合构象中。在APS上进行的SAXS实验将提供关键数据，以确定在存在和不存在ATP的情况下我们工程的HSP90分子的构象状态。结合目前正在进行的体内研究以分析激酶成熟，SAXS数据将为生物学和医学的基本过程提供重要的见解。