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

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

Nature biotechnology (1998-12-16)
C Klein, J I Paul, K Sauvé, M M Schmidt, L Arcangeli, J Ransom, J Trueheart, J P Manfredi, J R Broach, A J Murphy
摘要

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.

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MMK-1 trifluoroacetate, ≥95% (HPLC)