NMR structure and dynamics of the agonist dynorphin peptide bound to the human kappa opioid receptor.

نویسندگان

  • Casey O'Connor
  • Kate L White
  • Nathalie Doncescu
  • Tatiana Didenko
  • Bryan L Roth
  • Georges Czaplicki
  • Raymond C Stevens
  • Kurt Wüthrich
  • Alain Milon
چکیده

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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عنوان ژورنال:
  • Proceedings of the National Academy of Sciences of the United States of America

دوره 112 38  شماره 

صفحات  -

تاریخ انتشار 2015