NMR structure and dynamics of the agonist dynorphin peptide bound to the human kappa opiod receptor
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Date
2015-09-22
Publication Type
Journal Article
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yes
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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. 1H and 15N 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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published
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Volume
112 (38)
Pages / Article No.
11852 - 11857
Publisher
National Academy of Sciences
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Subject
GPCR activation; Transferred NOE; N-15 relaxation; Molecular dynamics simulations; Ligand binding affinity
Organisational unit
03129 - Wüthrich, Kurt (emeritus) / Wüthrich, Kurt (emeritus)