A Deep Hydrophobic Binding Cavity is the Main Interaction for Different Y₂R Antagonists

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• 作者：Kerstin Burkert ; Tristan Zellmann ; Dr. René ; Meier ; Dr. Anette Kaiser ; Dr. Jan Stichel ; Prof. Dr. Jens Meiler ; Dr. Gopi K. Mittapalli ; Prof. Dr. Edward Roberts and Prof. Dr. Annette G. Beck-Sickinger
• 刊名：ChemMedChem
• 出版年：2017
• 出版时间：January 5, 2017
• 年：2017
• 卷：12
• 期：1
• 页码：75-85
• 全文大小：1830K
• ISSN：1860-7187

文摘

The neuropeptide Y₂ receptor (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 Q^3.32, a position that has been shown to be crucial for binding of the amidated C terminus of NPY and thus for receptor activation.