Key result
Methyl 13C rotating frame relaxation dispersion NMR spectroscopy detected conformational dynamics on a time scale of approximately 130 microseconds in the substrate binding pocket of human FKBP12.
The study demonstrates the plasticity of the FKBP12 substrate binding pocket in the absence of substrate, suggesting that substrate recognition involves rapid relative movement of specific subdomains.
No immediate clinical implications for cardiovascular care; leaves open FKBP12 dynamics as a research target in cardiac signaling.
Transverse relaxation dispersion NMR spectroscopy can provide atom-specific information about time scales, populations, and the extent of structural reorganization in proteins under equilibrium conditions. A method is described that uses side-chain methyl groups as local reporters for conformational transitions taking place in the microsecond regime. The experiment measures carbon nuclear spin relaxation rates in the presence of continuous wave off-resonance irradiation, in proteins uniformly enriched with 13C, and partially randomly labeled with 2H. The method was applied to human FK-506 binding protein (FKBP12), which uses a common surface for binding substrates in its dual role as both an immunophilin and folding assistant. Conformational dynamics on a time scale of approximately 130 micros were detected for methyl groups located in the substrate binding pocket, demonstrating its plasticity in the absence of substrate. The spatial arrangement of affected side-chain atoms suggests that substrate recognition involves the rapid relative movement of the subdomain comprising residues Ala81-Thr96 and that the observed dynamics play an important role in facilitating the interaction of this protein with its many partners, including calcineurin.
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Brath et al. (2006) studied this question. Methyl 13C rotating frame relaxation dispersion NMR spectroscopy was evaluated on Conformational dynamics of human FKBP12. Methyl 13C rotating frame relaxation dispersion NMR spectroscopy detected conformational dynamics on a time scale of approximately 130 microseconds in the substrate binding pocket of human FKBP12.
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