Structural basis for ligand recognition of the neuropeptide Y Y2 receptor

Tingting Tang, Christin Hartig, Qiuru Chen, Wenli Zhao, Anette Kaiser, Xuefeng Zhang, Hui Zhang, Honge Qu, Cuiying Yi, Limin Ma, Shuo Han, Qiang Zhao (), Annette G. Beck-Sickinger () and Beili Wu ()
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Tingting Tang: Chinese Academy of Sciences
Christin Hartig: Leipzig University
Qiuru Chen: Chinese Academy of Sciences
Wenli Zhao: Chinese Academy of Sciences
Anette Kaiser: Leipzig University
Xuefeng Zhang: Chinese Academy of Sciences
Hui Zhang: Chinese Academy of Sciences
Honge Qu: Chinese Academy of Sciences
Cuiying Yi: Chinese Academy of Sciences
Limin Ma: Chinese Academy of Sciences
Shuo Han: Chinese Academy of Sciences
Qiang Zhao: Chinese Academy of Sciences
Annette G. Beck-Sickinger: Leipzig University
Beili Wu: Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract The human neuropeptide Y (NPY) Y2 receptor (Y2R) plays essential roles in food intake, bone formation and mood regulation, and has been considered an important drug target for obesity and anxiety. However, development of drugs targeting Y2R remains challenging with no success in clinical application yet. Here, we report the crystal structure of Y2R bound to a selective antagonist JNJ-31020028 at 2.8 Å resolution. The structure reveals molecular details of the ligand-binding mode of Y2R. Combined with mutagenesis studies, the Y2R structure provides insights into key factors that define antagonistic activity of diverse antagonists. Comparison with the previously determined antagonist-bound Y1R structures identified receptor-ligand interactions that play different roles in modulating receptor activation and mediating ligand selectivity. These findings deepen our understanding about molecular mechanisms of ligand recognition and subtype specificity of NPY receptors, and would enable structure-based drug design.

Date: 2021
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DOI: 10.1038/s41467-021-21030-9

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