Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 54, Issue 25, Pages 7446-7449Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201411688
Keywords
GPCRs; neuropeptide Y; NMR spectroscopy; peptide structure; receptors
Categories
Funding
- European Community
- Free State of Saxony [ESF 22117016, 24127009]
- German Research Foundation [SFB 1052A3, DFG BE1264/16]
- NIH [R01 DK097376]
- NSF [CHE 1305874]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1305874] Funding Source: National Science Foundation
- Office Of The Director
- Office Of Internatl Science &Engineering [1157751] Funding Source: National Science Foundation
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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 Y-2 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 a-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.
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