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Extension of Drosophila melanogaster life span with a GPCR peptide inhibitor

Ja, William W. and West, Anthony P., Jr. and Delker, Silvia L. and Bjorkman, Pamela J. and Benzer, Seymour and Roberts, Richard W. (2007) Extension of Drosophila melanogaster life span with a GPCR peptide inhibitor. Nature Chemical Biology, 3 (7). pp. 415-419. ISSN 1552-4450. PMCID PMC2803097. doi:10.1038/nchembio.2007.2. https://resolver.caltech.edu/CaltechAUTHORS:20170327-151553746

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[img] PDF (Supplementary Fig. 1 - Selected peptides recognize the full-length Methuselah receptor) - Supplemental Material
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[img] PDF (Supplementary Fig. 2 - Amino acid analysis of selected peptides) - Supplemental Material
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[img] PDF (Supplementary Fig. 3 - Peptide binding site is not localized to Methuselah Trp120) - Supplemental Material
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[img] PDF (Supplementary Fig. 4 - Expression of R8-12 extends Drosophila lifespan) - Supplemental Material
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[img] PDF (Supplementary Fig. 5 - Binding analysis of R8-04 to Methuselah by surface plasmon resonance) - Supplemental Material
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[img] PDF (Supplementary Table 1 - Selected peptide sequences from Methuselah selection) - Supplemental Material
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[img] PDF (Supplementary Table 2 - Crystallography data collection and refinement statistics) - Supplemental Material
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[img] PDF (Supplementary Methods) - Supplemental Material
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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/nchembio.2007.2DOIArticle
https://rdcu.be/bozavPublisherFree ReadCube access
http://www.nature.com/nchembio/journal/v3/n7/suppinfo/nchembio.2007.2_S1.htmlPublisherSupplementary Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803097/PubMed CentralArticle
ORCID:
AuthorORCID
Bjorkman, Pamela J.0000-0002-2277-3990
Roberts, Richard W.0000-0002-8587-5097
Additional Information:© 2007 Macmillan Publishers Limited. Received 8 May 2006; accepted 11 May 2007; published online 3 June 2007. We thank A.M. Giannetti for technical expertise on the Biacore; D.G. Myszka (University of Utah) for the SPR analysis software, Scrubber and CLAMP; M.I. Simon for use of the Flexstation automated fluorescence plate reader; T. Brummel and D. Walker for their technical expertise on the life span experiments; T.T. Takahashi and G.B. Carvalho for comments on the manuscript; and S. Cvejic and X.-Y. Huang (Cornell University Weill Medical College) for providing the HEK-Mth cell lines and details on their protocols. We are grateful to P.M. Snow (deceased, 2004) for his expertise in protein purification. This work was supported by grants from the US National Institutes of Health (R01 GM60416 to R.W.R. and R01 AG016630 to S.B.) and the Beckman Foundation (R.W.R.). W.W.J. was supported in part by a US Department of Defense National Defense Science and Engineering Graduate Fellowship, a Scholarship for Research in the Biology of Aging sponsored by the Glenn Foundation for Medical Research and the American Federation for Aging Research, and a John Douglas French Alzheimer's Foundation Postdoctoral Fellowship. A.P.W., Jr. was supported by a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund. The authors declare no competing financial interests.
Funders:
Funding AgencyGrant Number
NIHR01 GM60416
NIHR01 AG016630
Arnold and Mabel Beckman FoundationUNSPECIFIED
National Defense Science and Engineering Graduate (NDSEG) FellowshipUNSPECIFIED
Glenn Foundation for Medical ResearchUNSPECIFIED
American Federation for Aging ResearchUNSPECIFIED
John Douglas French Alzheimer's FoundationUNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Issue or Number:7
PubMed Central ID:PMC2803097
DOI:10.1038/nchembio.2007.2
Record Number:CaltechAUTHORS:20170327-151553746
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170327-151553746
Official Citation:Extension of Drosophila melanogaster life span with a GPCR peptide inhibitor William W Ja, Anthony P West, Jr, Silvia L Delker, Pamela J Bjorkman, Seymour Benzer & Richard W Roberts Nature Chemical Biology 3, 415 - 419 (2007) Published online: 3 June 2007 doi:10.1038/nchembio.2007.2
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75440
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:27 Mar 2017 22:29
Last Modified:15 Nov 2021 16:33

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