Membrane-induced structure of the mammalian tachykinin Neuropeptide gamma

  • Chandrashekar I
  • Dike A
  • Cowsik S
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Abstract

Neuropeptide gamma (NPγ) is a neurokinin-2 (NK-2) receptor selective agonist, which plays an important role in mediation of asthma and elicits a wide range of biological responses like bronchoconstriction, vasodepression and regulation of endocrine functions. The structure determination of this peptide agonist is important in understanding the molecular basis of peptide ligand recognition by the receptor and for rational drug design. In the present study we report the solution structure of NPγ characterized by circular dichroism (CD) spectropolarimetry and 2D1H NMR spectroscopy in both aqueous and membrane mimetic solvents. Effect of calcium ions on the conformation of NPγ was also studied using CD spectropolarimetry. Sequence-specific resonance assignments of protons have been made with the aid of correlation spectroscopy experiments and nuclear Overhauser effect spectroscopy experiments. The distance constraints obtained from the NMR data have been utilized to generate a family of structures, which have been refined using restrained energy minimization and dynamics. These data show that in water NPγ prefers to be in an extended chain conformation whereas a helical conformation is induced in the central core and the C-terminal region of the peptide (K13-M21) in the presence of perdeuterated dodecylphosphocholine micelles, a membrane model system. A type II′ β turn from H9 to R11 precedes the helical core in the C-terminus of NPγ. N-terminus of NPγ also displays some degree of order and a possible turn structure. Conformation adopted by NPγ in presence of lipid micelles represents a structural motif typical of NK-2 selective agonists and is similar to that observed for Neurokinin A in hydrophobic environment. The observed conformational features have been correlated to the binding ability and biological activity of NPγ. © 2004 Elsevier Inc. All rights reserved.

Author-supplied keywords

  • 3D structure
  • Bioactive peptide
  • NK-2 selective agonists
  • NMR spectroscopy
  • Neuropeptide gamma
  • Peptide-membrane interaction
  • Tachykinins

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Authors

  • Indu R. Chandrashekar

  • Anjali Dike

  • Sudha M. Cowsik

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