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

Kaiser A, Müller P, Zellmann T, Scheidt HA, Thomas L, Bosse M, Meier R, Meiler J, Huster D, Beck-Sickinger AG, Schmidt P
Angew Chem Int Ed Engl. 2015 54 (25): 7446-9

PMID: 25924821 · PMCID: PMC5497120 · DOI:10.1002/anie.201411688

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 T(32) to provide optimal contacts in a deep binding pocket within the transmembrane bundle of the Y2R.

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

MeSH Terms (10)

Amino Acid Sequence Binding Sites Humans Molecular Docking Simulation Molecular Sequence Data Neuropeptide Y Nuclear Magnetic Resonance, Biomolecular Protein Binding Protein Structure, Secondary Receptors, Neuropeptide Y

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