Zusammenfassung
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 & ...
Zusammenfassung
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.
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