NMR analysis of Caenorhabditis elegans FLP-18 neuropeptides: implications for NPR-1 activation

Biochemistry. 2006 Jun 20;45(24):7586-97. doi: 10.1021/bi0603928.


Phe-Met-Arg-Phe-NH2 (FMRFamide)-like peptides (FLPs) are the largest neuropeptide family in animals, particularly invertebrates. FLPs are characterized by a C-N-terminal gradient of decreasing amino acid conservation. Neuropeptide receptor 1 (NPR-1) is a G-protein coupled receptor (GPCR), which has been shown to be a strong regulator of foraging behavior and aggregation responses in Caenorhabditis elegans. Recently, ligands for NPR-1 were identified as neuropeptides coded by the precursor genes flp-18 and flp-21 in C. elegans. The flp-18 gene encodes eight FLPs including DFDGAMPGVLRF-NH2 and EMPGVLRF-NH2. These peptides exhibit considerably different activities on NPR-1, with the longer one showing a lower potency. We have used nuclear magnetic resonance and biological activity to investigate structural features that may explain these activity differences. Our data demonstrate that long-range electrostatic interactions exist between N-terminal aspartates and the C-terminal penultimate arginine as well as N-terminal hydrogen-bonding interactions that form transient loops within DFDGAMPGVLRF-NH2. We hypothesize that these loops, along with peptide charge, diminish the activity of this peptide on NPR-1 relative to that of EMPGVLRF-NH2. These results provide some insight into the large amino acid diversity in FLPs.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Arginine / chemistry
  • Aspartic Acid / chemistry
  • Caenorhabditis elegans / chemistry
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Conserved Sequence
  • Dose-Response Relationship, Drug
  • Female
  • Genes, Helminth
  • Helminth Proteins / analysis*
  • Helminth Proteins / chemistry
  • Helminth Proteins / genetics
  • Helminth Proteins / metabolism
  • Helminth Proteins / pharmacology
  • Hydrogen Bonding
  • Hydrogen-Ion Concentration
  • Molecular Sequence Data
  • Neuropeptides / analysis*
  • Neuropeptides / chemistry
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Neuropeptides / pharmacology
  • Nuclear Magnetic Resonance, Biomolecular*
  • Oocytes / metabolism
  • Protein Structure, Secondary
  • Receptors, Neuropeptide Y / genetics
  • Receptors, Neuropeptide Y / metabolism*
  • Static Electricity
  • Xenopus laevis


  • Caenorhabditis elegans Proteins
  • Helminth Proteins
  • NPR-1 protein, C elegans
  • Neuropeptides
  • Receptors, Neuropeptide Y
  • Aspartic Acid
  • Arginine