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

Academic Article
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Overview

authors

  • O'Connor, C.
  • White, K. L.
  • Doncescu, N.
  • Didenko, T.
  • Roth, B. L.
  • Czaplicki, G.
  • Stevens, Raymond
  • Wuthrich, Kurt
  • Milon, A.

publication date

  • September 2015

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

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.
  • 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.

subject areas

  • Amino Acid Sequence
  • Dynorphins
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Nitrogen Isotopes
  • Peptide Fragments
  • Peptides
  • Piperidines
  • Protein Binding
  • Protein Structure, Secondary
  • Receptors, Opioid, kappa
  • Tetrahydroisoquinolines
  • Time Factors
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Research

keywords

  • GPCR activation
  • N-15 relaxation
  • ligand binding affinity
  • molecular dynamics simulations
  • transferred NOE
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Identity

PubMed Central ID

  • PMC4586840

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1510117112

PubMed ID

  • 26372966
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Additional Document Info

start page

  • 11852

end page

  • 11857

volume

  • 112

issue

  • 38

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