Friday, October 24, 2008

J. Am. Chem. Soc., 130 (43), 14060–14061, 2008.

Dynamics of Ligand Binding from 13C NMR Relaxation Dispersion at Natural Abundance
John S. Zintsmaster, Brian D. Wilson, and Jeffrey W. Peng*

We show that Carr−Purcell−Meiboom−Gill (CPMG) 13Cα NMR relaxation dispersion measurements are a viable means for profiling μs−ms ligand dynamics involved in receptor binding. Critically, the dispersion is at natural 13C abundance; this matches typical pharmaceutical research settings in which ligand isotope-labeling is often impractical. The dispersion reveals ligand 13Cα nuclei that experience μs−ms modulation of their chemical shifts due to binding. 13Cα shifts are dominated by local torsion angles φ, ψ, χ1; hence, these experiments identify flexible torsion angles that may assist complex formation. Since the experiments detect the ligand, they are viable even in the absence of a receptor structure. The μs−ms dynamic information gained helps establish flexibility−activity relationships. We apply these experiments to study the binding of a phospho-peptide substrate ligand to the peptidyl-prolyl isomerase Pin1.

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