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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR015301-09
Application #
8361616
Study Section
Special Emphasis Panel (ZRG1-BCMB-K (40))
Project Start
2011-04-01
Project End
2012-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
9
Fiscal Year
2011
Total Cost
$27,437
Indirect Cost
Name
Cornell University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Fallas, Jorge A; Ueda, George; Sheffler, William et al. (2017) Computational design of self-assembling cyclic protein homo-oligomers. Nat Chem 9:353-360
Krotee, Pascal; Rodriguez, Jose A; Sawaya, Michael R et al. (2017) Atomic structures of fibrillar segments of hIAPP suggest tightly mated ?-sheets are important for cytotoxicity. Elife 6:
Dhayalan, Balamurugan; Mandal, Kalyaneswar; Rege, Nischay et al. (2017) Scope and Limitations of Fmoc Chemistry SPPS-Based Approaches to the Total Synthesis of Insulin Lispro via Ester Insulin. Chemistry 23:1709-1716
Bale, Jacob B; Gonen, Shane; Liu, Yuxi et al. (2016) Accurate design of megadalton-scale two-component icosahedral protein complexes. Science 353:389-94
AhYoung, Andrew P; Koehl, Antoine; Vizcarra, Christina L et al. (2016) Structure of a putative ClpS N-end rule adaptor protein from the malaria pathogen Plasmodium falciparum. Protein Sci 25:689-701
Hancock, Stephen P; Stella, Stefano; Cascio, Duilio et al. (2016) DNA Sequence Determinants Controlling Affinity, Stability and Shape of DNA Complexes Bound by the Nucleoid Protein Fis. PLoS One 11:e0150189
Taylor, Noah D; Garruss, Alexander S; Moretti, Rocco et al. (2016) Engineering an allosteric transcription factor to respond to new ligands. Nat Methods 13:177-83
Kattke, Michele D; Chan, Albert H; Duong, Andrew et al. (2016) Crystal Structure of the Streptomyces coelicolor Sortase E1 Transpeptidase Provides Insight into the Binding Mode of the Novel Class E Sorting Signal. PLoS One 11:e0167763
Jorda, J; Leibly, D J; Thompson, M C et al. (2016) Structure of a novel 13 nm dodecahedral nanocage assembled from a redesigned bacterial microcompartment shell protein. Chem Commun (Camb) 52:5041-4
Dhayalan, Balamurugan; Fitzpatrick, Ann; Mandal, Kalyaneswar et al. (2016) Efficient Total Chemical Synthesis of (13) C=(18) O Isotopomers of Human Insulin for Isotope-Edited FTIR. Chembiochem 17:415-20

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