Identifizierung der Rezeptorinteraktion von RF-amid-Peptiden auf molekularer Ebene
Final Report Abstract
The aim of the project was to investigate the role of the conserved residue Asp/Glu 6.59 in RF-amide receptors that we previously had identified for the neuropeptide Y system. We aimed to study this by ligand variations as well as receptor mutagenesis in combination with advanced molecular modelling in collaboration with Vanderbilt University (J. Meiler). The data were convincing and clearly supported our hypothesis of the role of the conserved residue Asp/Glu 6.59. Furthermore, we could analyze the binding mode of known and new antagonists of the RF-amide receptor system and compare it with antagonists for Y1 that also display antagonistic properties for the NPFF-system. As some money was left we investigated the last aspect, whether Y2-receptors share the same binding site for antagonists, and clearly can positively answer this question as demonstrated in our latest and just accepted publication. Accordingly, we identified a common structure of the antagonist binding for Y- and RF-amide receptors that play an important role in energy homeostasis, regeneration and tumor.
Publications
- Structure-activity studies of RFamide peptides reveal subtype-selective activation of neuropeptide FF1 and FF2 receptors. ChemMedChem. 2011 Jun 6;6(6):1081-93
Findeisen M, Rathmann D, Beck-Sickinger AG
- Ligand-mimicking receptor variant discloses binding and activation mode of prolactin-releasing peptide. J Biol Chem. 2012 Sep 14;287(38):32181-94
Rathmann D, Lindner D, DeLuca SH, Kaufmann KW, Meiler J, Beck-Sickinger AG
(See online at https://doi.org/10.1074/jbc.M112.349852) - Selective mode of action of guanidine-containing non-peptides at human NPFF receptors. J Med Chem. 2012 Jul 12;55(13):6124-36
Findeisen M, Würker C, Rathmann D, Meier R, Meiler J, Olsson R, Beck-Sickinger AG
(See online at https://doi.org/10.1021/jm300535s) - In vitro modification of substituted cysteines as tool to study receptor functionality and structure-activity relationships. Anal Biochem. 2013 Aug 15;439(2):173-83
Rathmann D, Pedragosa-Badia X, Beck-Sickinger AG
(See online at https://doi.org/10.1016/j.ab.2013.04.015) - The activity of prolactin releasing peptide correlates with its helicity. Biopolymers. 2013 May;99(5):314-25
Deluca SH, Rathmann D, Beck-Sickinger AG, Meiler J
(See online at https://doi.org/10.1002/bip.22162) - , Deep Hydrophobic Binding Cavity is the Main Interaction of Different Y2R Antagonists. ChemMedChem. 2016 Nov 22
Burkert K, Zellmann T, Kaiser A, Meier R, Stichel J, Meiler J, Mittapalli GK, Roberts E. Beck-Sickinger AG
(See online at https://doi.org/10.1002/cmdc.201600433)
