A Deep Hydrophobic Binding Cavity is the Main Interaction for Different Y R Antagonists.

Burkert K, Zellmann T, Meier R, Kaiser A, Stichel J, Meiler J, Mittapalli GK, Roberts E, Beck-Sickinger AG
ChemMedChem. 2017 12 (1): 75-85

PMID: 27874262 · DOI:10.1002/cmdc.201600433

The neuropeptide Y receptor (Y R) is involved in various pathophysiological processes such as epilepsy, mood disorders, angiogenesis, and tumor growth. Therefore, the Y R 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 Y R in vitro and in vivo. In this study, several residues crucial to the interaction of BIIE0246 and SF-11 derivatives with Y R were investigated by signal transduction assays. Using the experimental results as constraints, the antagonists were docked into a comparative structural model of the Y R. 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 Q , a position that has been shown to be crucial for binding of the amidated C terminus of NPY and thus for receptor activation.

© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

MeSH Terms (15)

Animals Arginine Benzazepines Binding Sites Cells, Cultured Cercopithecus aethiops COS Cells Dose-Response Relationship, Drug HEK293 Cells Humans Hydrophobic and Hydrophilic Interactions Molecular Docking Simulation Molecular Structure Receptors, Neuropeptide Y Structure-Activity Relationship

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