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- Title
Unwinding of the C-Terminal Residues of Neuropeptide Y is critical for Y<sub>2</sub> Receptor Binding and Activation.
- Authors
Kaiser, Anette; Meier, Rene; Beck-Sickinger, Annette G.; Zellmann, Tristan; Müller, Paul; Scheidt, Holger A.; Thomas, Lars; Bosse, Mathias; Huster, Daniel; Schmidt, Peter; Meiler, Jens
- Abstract
Despite recent breakthroughs in the structural characterization of G-protein-coupled receptors (GPCRs), there is only sparse data on how GPCRs recognize larger peptide ligands. NMR spectroscopy, molecular modeling, and double-cycle mutagenesis studies were integrated to obtain a structural model of the peptide hormone neuropeptide Y (NPY) bound to its human G-protein-coupled Y2 receptor (Y2R). Solid-state NMR measurements of specific isotope-labeled NPY in complex with in vitro folded Y2R reconstituted into phospholipid bicelles provided the bioactive structure of the peptide. Guided by solution NMR experiments, it could be shown that the ligand is tethered to the second extracellular loop by hydrophobic contacts. The C-terminal α-helix of NPY, which is formed in a membrane environment in the absence of the receptor, is unwound starting at T32 to provide optimal contacts in a deep binding pocket within the transmembrane bundle of the Y2R.
- Subjects
G protein coupled receptors; NEUROPEPTIDE Y; C-terminal residues; PEPTIDE receptors; NUCLEAR magnetic resonance spectroscopy; BINDING sites
- Publication
Angewandte Chemie International Edition, 2015, Vol 54, Issue 25, p7446
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201411688