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Unwinding of the C-Terminal Residues of Neuropeptide Y is critical for Y? Receptor Binding and Activation.

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 ?-helix of NPY, which is formed in a membrane environment in the absence of the receptor, is unwound starting at T(32) to provide optimal contacts in a deep binding pocket within the transmembrane bundle of the Y2R.

SUBMITTER: Kaiser A

PROVIDER: S-EPMC5497120 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Unwinding of the C-Terminal Residues of Neuropeptide Y is critical for Y₂ Receptor Binding and Activation.

Kaiser Anette A Müller Paul P Zellmann Tristan T Scheidt Holger A HA Thomas Lars L Bosse Mathias M Meier Rene R Meiler Jens J Huster Daniel D Beck-Sickinger Annette G AG Schmidt Peter P

Angewandte Chemie (International ed. in English) 20150429 25

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 recons ...[more]

PMID: 25924821

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Dataset Information

Unwinding of the C-Terminal Residues of Neuropeptide Y is critical for Y? Receptor Binding and Activation.

Publications

Unwinding of the C-Terminal Residues of Neuropeptide Y is critical for Y₂ Receptor Binding and Activation.

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