Plut, Eva and Calderon, Jacqueline C. and Stanojlovic, Vesna and Gattor, Albert O. and Hoering, Carina and Humphrys, Laura J. and Konieczny, Adam and Kerres, Sabine and Schubert, Mario and Keller, Max and Cabrele, Chiara and Clark, Timothy and Reiser, Oliver (2023) Stereochemistry-Driven Interactions of α,γ-Peptide Ligands with the Neuropeptide Y Y4-Receptor. JOURNAL OF MEDICINAL CHEMISTRY, 66 (14). pp. 9642-9657. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)Abstract
The G-protein-coupledY(4)-receptor (Y4R) andits endogenous ligand, pancreatic polypeptide (PP), suppress appetitein response to food intake and, thus, are attractive drug targetsfor body-weight control. The C-terminus of human PP (hPP), T-32-R-33-P-34-R-35-Y-36-NH (2), penetrates deep into the binding pocketwith its tyrosine-amide and di-arginine motif. Here, we present twoC-terminally amidated & alpha;,& gamma;-hexapeptides (1a/b) with sequence Ac-R-31-& gamma;-CBAA(32)-R-33-L-34-R-35-Y-36-NH (2), where & gamma;-CBAAis the (1R,2S,3R)-configured 2-(aminomethyl)-3-phenylcyclobutanecarboxyl moiety (1a) or its mirror image (1b). Both peptides bindthe Y4R (K (i) of 1a/b: 0.66/12 nM) and act as partial agonists (intrinsicactivity of 1a/b: 50/39%). Their induced-fitbinding poses in the Y4R pocket are unique and build ligand-receptorcontacts distinct from those of the C-terminus of the endogenous ligandhPP. We conclude that energetically favorable interactions, althoughthey do not match those of the native ligand hPP, still guaranteehigh binding affinity (with 1a rivaling hPP) but notthe maximum receptor activation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Y-1 RECEPTOR ANTAGONISTS; PANCREATIC-POLYPEPTIDE; AMINO-ACIDS; SELECTIVE AGONIST; CHEMICAL-SHIFTS; LOCAL-STRUCTURE; UCSF CHIMERA; FOOD-INTAKE; NPY; PROTEIN; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institut für Organische Chemie > Lehrstuhl Prof. Dr. Oliver Reiser |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 11 Mar 2024 13:36 |
| Last Modified: | 11 Mar 2024 13:49 |
| URI: | https://pred.uni-regensburg.de/id/eprint/59655 |
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