Identification of surrogate agonists for the human FPRL-1 receptor by autocrine selection in yeast

Nat Biotechnol. 1998 Dec;16(13):1334-7. doi: 10.1038/4310.


We describe a procedure for isolating agonists for mammalian G protein-coupled receptors of unknown function. Human formyl peptide receptor like-1 (FPRL-1) receptor, originally identified as an orphan G protein-coupled receptor related to the formyl peptide receptor (FPR1), was expressed in Saccharomyces cells designed to couple receptor activation to histidine prototrophy. Selection for histidine prototrophs among transformants obtained with a plasmid-based library encoding random peptides identified six different agonists, each of whose production yielded autocrine stimulation of the receptor expressed in yeast. A synthetic version of each peptide promoted activation of FPRL-1 expressed in human embryonic kidney (HEK293) cells, and five of the peptides exhibited significant selectivity for activation of FPRL-1 relative to FPR1. One selective peptide was tested and found to mobilize calcium in isolated human neutrophils. This demonstrates that stimulation of FPRL-1 results in neutrophil activation and suggests that the receptor functions as a component of the inflammatory response. This autocrine selection protocol may be a generally applicable method for providing pharmacological tools to evaluate the physiological roles of the growing number of mammalian orphan G protein-coupled receptors.

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Humans
  • Ligands
  • Molecular Sequence Data
  • Monocytes / metabolism
  • N-Formylmethionine Leucyl-Phenylalanine / metabolism
  • Neutrophils / metabolism
  • Peptides / chemistry
  • Peptides / metabolism
  • Receptors, Formyl Peptide
  • Receptors, Immunologic / agonists*
  • Receptors, Immunologic / metabolism
  • Receptors, Peptide / agonists*
  • Receptors, Peptide / metabolism
  • Recombinant Proteins / agonists
  • Recombinant Proteins / metabolism
  • Saccharomyces cerevisiae / genetics*


  • Ligands
  • Peptides
  • Receptors, Formyl Peptide
  • Receptors, Immunologic
  • Receptors, Peptide
  • Recombinant Proteins
  • N-Formylmethionine Leucyl-Phenylalanine