RABBIT SKELETAL RYANODINE RECEPTOR CRYSTAL STRUCTURE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 本研究的总体目标是首次在原子水平上确定骨骼肌(RyR1)和心肌(RyR2)兴奋收缩(EC)偶联所需的全长钙释放通道/RyR的结构。我们的目标是克服在RyRs领域取得进展的这一关键障碍，并扩大我们对细胞内钙释放通道的结构/功能关系的理解，以及蛋白质-蛋白质相互作用、翻译后修饰、致病突变和药物调节RyR通道功能的机制。 这些研究的目的是提供第一个高分辨率的全长天然RyR1通道的快照，并确定该通道的关键功能区域，这些区域将对骨骼肌和心肌钙释放通道和EC偶联产生巨大影响。 RyR1和RyR2的原子分辨率信息仅限于氨基末端的小区域，缺乏完整受体的高分辨率信息严重阻碍了对RyRs在生理和疾病状态下功能的详细了解。这项研究将提供重要的新的结构信息，有助于解决许多关于RyRs在正常生理中的调节及其与疾病相关的功能障碍的悬而未决的问题。有关RyRs的结构数据将揭示突变如何导致通道功能障碍和肌肉紊乱，以及药物可能如何修改功能障碍的通道以改善结果。这些研究可能导致设计更好、更有效的治疗骨骼肌和心肌疾病的方法，其基础是将药物对接在RyR通道上的结合部位。

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. The overall objective of this study is to determine, for the first time at an atomic level resolution, the structure of full length Ca2+ release channel / ryanodine receptor (RyR) that is required for excitation-contraction (EC) coupling in skeletal (RyR1) and in cardiac (RyR2) muscles. Our aims are designed to overcome this critical barrier to progress in the RyRs field and to expand our understandings of the structure/function relationships of intracellular Ca2+ release channels and the mechanisms by which protein-protein interactions, post-translational modifications, disease causing mutations and drugs modulate the RyR channel function. The proposed studies are designed to provide the first high-resolution snapshot of the full-length native RyR1 channels and identify key functional regions of the channel that will have an enormous impact on the fields of skeletal and cardiac muscles calcium release channels and EC coupling. Atomic resolution information for RyR1 and RyR2 has been limited to small regions of the amino terminus and the lack of high-resolution information on the intact receptor has severely hampered a detailed understanding of RyRs function in physiological and diseased states. This study will provide important new structural information that will help address many of the outstanding questions concerning the regulation of RyRs in normal physiology and its dysfunction related to diseases. Structural data on RyRs will shed light on how mutations cause channel dysfunction and muscle disorders, and potentially how drugs modify the dysfunctional channels to improve outcome. These studies may lead to the design of better and more effective therapies for skeletal and cardiac muscle deseases based on the docking of drugs in their binding sites on the RyR channel.