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.
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