Letter abstract
Nature Chemical Biology 3, 415 - 419 (2007)
Published online: 3 June 2007 | doi:10.1038/nchembio.2007.2
Extension of Drosophila melanogaster life span with a GPCR peptide inhibitor
William W Ja1, Anthony P West, Jr1, Silvia L Delker1,4, Pamela J Bjorkman1,2, Seymour Benzer1 & Richard W Roberts3
G protein–coupled receptors (GPCRs) mediate signaling from extracellular ligands to intracellular signal transduction proteins1. Methuselah (Mth) is a class B (secretin-like) GPCR, a family typified by their large, ligand-binding, N-terminal extracellular domains2. Downregulation of mth increases the life span of Drosophila melanogaster3; inhibitors of Mth signaling should therefore enhance longevity. We used mRNA display selection4, 5 to identify high-affinity (Kd = 15 to 30 nM) peptide ligands that bind to the N-terminal ectodomain of Mth. The selected peptides are potent antagonists of Mth signaling, and structural studies suggest that they perturb the interface between the Mth ecto- and transmembrane domains. Flies constitutively expressing a Mth antagonist peptide have a robust life span extension, which suggests that the peptides inhibit Mth signaling in vivo. Our work thus provides new life span–extending ligands for a metazoan and a general approach for the design of modulators of this important class of GPCRs.
- Division of Biology, 1200 E. California Blvd. 156-29, California Institute of Technology, Pasadena, California 91125, USA.
- Howard Hughes Medical Institute, 1200 E. California Blvd. 156-29, California Institute of Technology, Pasadena, California 91125, USA.
- Departments of Chemistry, Chemical Engineering, and Biology, University of Southern California, Los Angeles, California 90089, USA.
- Present address: Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92617, USA.
Correspondence to: Richard W Roberts3 e-mail: richard.roberts@usc.edu
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