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Angew Chem Int Ed Engl. 2015 Jun 15;54(25):7446-9. doi: 10.1002/anie.201411688. Epub 2015 Apr 29.

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

Author information

1
Institut für Biochemie, Universität Leipzig, Brüderstraße 34, 04103 Leipzig (Germany).
2
Institut für Medizinische Physik und Biophysik, Universität Leipzig, Härtelstraße 16-18, 04107 Leipzig (Germany).
3
Center for Structural Biology, Vanderbilt University, 465 21stAve South, Nashville, TN 37203 (USA).
4
Institut für Medizinische Physik und Biophysik, Universität Leipzig, Härtelstraße 16-18, 04107 Leipzig (Germany). peter.schmidt@medizin.uni-leipzig.de.

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

KEYWORDS:

GPCRs; NMR spectroscopy; neuropeptide Y; peptide structure; receptors

PMID:
25924821
PMCID:
PMC5497120
DOI:
10.1002/anie.201411688
[Indexed for MEDLINE]
Free PMC Article

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