2PZX

Structure of the methuselah ectodomain with peptide inhibitor

Summary for 2PZX

• Entry DOI: 10.2210/pdb2pzx/pdb
• Related: 1FJR
• Descriptor: G-protein coupled receptor Mth (1 entity in total)
• Functional Keywords: gpcr g protein-coupled receptor ectodomain, signaling protein
• Biological source: Drosophila melanogaster (fruit fly)
• Cellular location: Cell membrane ; Multi-pass membrane protein : O97148
• Total number of polymer chains: 4
• Total formula weight: 87343.24

Authors

West Jr., A.P.,Ja, W.W.,Delker, S.L.,Bjorkman, P.J.,Benzer, S.,Roberts, R.W. (deposition date: 2007-05-18, release date: 2007-08-28, Last modification date: 2024-11-20)

Primary citation

Ja, W.W.,West, A.P.,Delker, S.L.,Bjorkman, P.J.,Benzer, S.,Roberts, R.W.
Extension of Drosophila melanogaster life span with a GPCR peptide inhibitor.
Nat.Chem.Biol., 3:415-419, 2007

PubMed 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.

PubMed: 17546039
DOI: 10.1038/nchembio.2007.2

Experimental method

X-RAY DIFFRACTION (3.5 Å)