Extension of Drosophila melanogaster life span with a GPCR peptide inhibitor.
G protein-coupled receptors (GPCRs) mediate signaling from extracellular ligands to intracellular signal transduction proteins. Methuselah (Mth) is a class B (secretin-like) GPCR, a family typified by their large, ligand-binding, N-terminal extracellular domains. Downregulation of mth increases the life span of Drosophila melanogaster; inhibitors of Mth signaling should therefore enhance longevity. We used mRNA display selection to identify high-affinity (K(d) = 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.
Ja
William W
WW
Division of Biology, 1200 E. California Blvd. 156-29, California Institute of Technology, Pasadena, California 91125, USA.
West
Anthony P
AP
Delker
Silvia L
SL
Bjorkman
Pamela J
PJ
Benzer
Seymour
S
Roberts
Richard W
RW
D000595:Amino Acid Sequence; D000818:Animals; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism; D008024:Ligands; D008136:Longevity / Q000187:drug effects; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
D029721:Drosophila Proteins; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C115381:mth protein, Drosophila