Structural basis for ligand recognition of the neuropeptide Y Y2 receptor

Tingting Tang,Hui Zhang,Limin Ma,Beili Wu,Qiuru Chen,Wenli Zhao,Xuefeng Zhang,Anette Kaiser,Honge Qu,Christin Hartig,Cuiying Yi,Shuo Han,Qiang Zhao,Annette G Beck-Sickinger

doi:10.1038/s41467-021-21030-9

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.

Highlights

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
Comparison of the Y2R–JNJ-31020028 structure and the previously determined Y1 receptor (Y1R) structures reveals ligand-binding pockets differing in shape (Fig. 4a–c)
JNJ-31020028 and the Y1R antagonists UR-MK299 and BMS-193885 share a similar binding site at the bottom of the ligand-binding cavity bordered by helices III–VI (Fig. 4d, e)

Summary

Introduction

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. 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. Crystal structures of Y1 receptor (Y1R) bound to two structurally diverse antagonists were recently determined, providing molecular details of ligand recognition and selectivity of a NPY receptor[13]. Together with extensive functional studies, our results provide key insights into the structural basis of Y2R ligand-binding mode and NPY receptor subtype specificity

Methods

Results

Conclusion