CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai, 201203, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai, 201203, China.
Nat Commun. 2021 Feb 2;12(1):737. doi: 10.1038/s41467-021-21030-9.
The human neuropeptide Y (NPY) Y receptor (YR) 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 YR remains challenging with no success in clinical application yet. Here, we report the crystal structure of YR bound to a selective antagonist JNJ-31020028 at 2.8 Å resolution. The structure reveals molecular details of the ligand-binding mode of YR. Combined with mutagenesis studies, the YR structure provides insights into key factors that define antagonistic activity of diverse antagonists. Comparison with the previously determined antagonist-bound YR 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.
人类神经肽 Y（NPY）Y 受体（YR）在食物摄入、骨形成和情绪调节中发挥着重要作用，被认为是肥胖和焦虑的重要药物靶点。然而，针对 YR 的药物开发仍然具有挑战性，目前尚未在临床应用中取得成功。在这里，我们报告了与选择性拮抗剂 JNJ-31020028 结合的 YR 的晶体结构，分辨率为 2.8Å。该结构揭示了 YR 的配体结合模式的分子细节。结合突变研究，YR 结构为不同拮抗剂的拮抗活性提供了关键因素的深入了解。与以前确定的结合拮抗剂的 YR 结构的比较确定了在调节受体激活和介导配体选择性方面发挥不同作用的受体-配体相互作用。这些发现加深了我们对配体识别和 NPY 受体亚型特异性的分子机制的理解，并将能够进行基于结构的药物设计。
