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  • Title: NMR structure and dynamics of the agonist dynorphin peptide bound to the human kappa opioid receptor.
    Author: O'Connor C, White KL, Doncescu N, Didenko T, Roth BL, Czaplicki G, Stevens RC, Wüthrich K, Milon A.
    Journal: Proc Natl Acad Sci U S A; 2015 Sep 22; 112(38):11852-7. PubMed ID: 26372966.
    Abstract:
    The structure of the dynorphin (1-13) peptide (dynorphin) bound to the human kappa opioid receptor (KOR) has been determined by liquid-state NMR spectroscopy. (1)H and (15)N chemical shift variations indicated that free and bound peptide is in fast exchange in solutions containing 1 mM dynorphin and 0.01 mM KOR. Radioligand binding indicated an intermediate-affinity interaction, with a Kd of ∼200 nM. Transferred nuclear Overhauser enhancement spectroscopy was used to determine the structure of bound dynorphin. The N-terminal opioid signature, YGGF, was observed to be flexibly disordered, the central part of the peptide from L5 to R9 to form a helical turn, and the C-terminal segment from P10 to K13 to be flexibly disordered in this intermediate-affinity bound state. Combining molecular modeling with NMR provided an initial framework for understanding multistep activation of a G protein-coupled receptor by its cognate peptide ligand.
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