title: A Deep Hydrophobic Binding Cavity is the Main Interaction for Different Y2R Antagonists.
abstract: The neuropeptide Y2receptor (Y2R) is involved in various pathophysiological processes such as epilepsy, mood disorders, angiogenesis, and tumor growth. Therefore, the Y2R is an interesting target for drug development. A detailed understanding of the binding pocket could facilitate the development of highly selective antagonists to study the role of Y2R in vitro and in vivo. In this study, several residues crucial to the interaction of BIIE0246 and SF-11 derivatives with Y2R were investigated by signal transduction assays. Using the experimental results as constraints, the antagonists were docked into a comparative structural model of the Y2R. Despite differences in size and structure, all three antagonists display a similar binding site, including a deep hydrophobic cavity formed by transmembrane helices (TM) 4, 5, and 6, as well as a hydrophobic patch at the top of TM2 and 7. Additionally, we suggest that the antagonists block Q3.32, a position that has been shown to be crucial for binding of the amidated C terminus of NPY and thus for receptor activation.
authors.affiliation: Faculty of Biosciences, Pharmacy and Psychology, Leipzig University, Institute of Biochemistry, Brüderstr. 34, 04103, Leipzig, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Burkert
authors.affiliation: Faculty of Biosciences, Pharmacy and Psychology, Leipzig University, Institute of Biochemistry, Brüderstr. 34, 04103, Leipzig, Germany.
authors.forename: Tristan
authors.initials: T
authors.lastname: Zellmann
authors.affiliation: Faculty of Biosciences, Pharmacy and Psychology, Leipzig University, Institute of Biochemistry, Brüderstr. 34, 04103, Leipzig, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Meier
authors.affiliation: Faculty of Biosciences, Pharmacy and Psychology, Leipzig University, Institute of Biochemistry, Brüderstr. 34, 04103, Leipzig, Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Kaiser
authors.affiliation: Faculty of Biosciences, Pharmacy and Psychology, Leipzig University, Institute of Biochemistry, Brüderstr. 34, 04103, Leipzig, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Stichel
authors.affiliation: Center for Structural Biology, Vanderbilt University, 465 21st Avenue South, Nashville, TN, 37203, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Meiler
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Gopi K
authors.initials: GK
authors.lastname: Mittapalli
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Roberts
authors.affiliation: Faculty of Biosciences, Pharmacy and Psychology, Leipzig University, Institute of Biochemistry, Brüderstr. 34, 04103, Leipzig, Germany.
authors.forename: Annette G
authors.identifier: 0000-0003-4560-8020
authors.initials: AG
authors.lastname: Beck-Sickinger
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D001552:Benzazepines / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D001552:Benzazepines; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D001120:Arginine; C403256:BIIE 0246
keywords: G protein-coupled receptors; antagonists; binding models; neuropeptide Y