Park Chaehee, Kim Jinuk, Ko Seung-Bum, Choi Yeol Kyo, Jeong Hyeongseop, Woo Hyeonuk, Kang Hyunook, Bang Injin, Kim Sang Ah, Yoon Tae-Young, Seok Chaok, Im Wonpil, Choi Hee-Jung
Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
Departments of Biological Sciences and Chemistry, Lehigh University, Bethlehem, PA, 18015, USA.
Nat Commun. 2022 Feb 14;13(1):853. doi: 10.1038/s41467-022-28510-6.
Neuropeptide Y (NPY) is highly abundant in the brain and involved in various physiological processes related to food intake and anxiety, as well as human diseases such as obesity and cancer. However, the molecular details of the interactions between NPY and its receptors are poorly understood. Here, we report a cryo-electron microscopy structure of the NPY-bound neuropeptide Y1 receptor (YR) in complex with G protein. The NPY C-terminal segment forming the extended conformation binds deep into the YR transmembrane core, where the amidated C-terminal residue Y36 of NPY is located at the base of the ligand-binding pocket. Furthermore, the helical region and two N-terminal residues of NPY interact with YR extracellular loops, contributing to the high affinity of NPY for YR. The structural analysis of NPY-bound YR and mutagenesis studies provide molecular insights into the activation mechanism of YR upon NPY binding.
神经肽Y（NPY）在大脑中含量极高，参与与食物摄入和焦虑相关的各种生理过程，以及肥胖和癌症等人类疾病。然而，NPY与其受体之间相互作用的分子细节仍知之甚少。在此，我们报告了结合NPY的神经肽Y1受体（YR）与G蛋白复合物的冷冻电镜结构。形成延伸构象的NPY C末端片段深入结合到YR跨膜核心，其中NPY的酰胺化C末端残基Y36位于配体结合口袋底部。此外，NPY的螺旋区域和两个N末端残基与YR细胞外环相互作用，有助于NPY对YR的高亲和力。结合NPY的YR的结构分析和诱变研究为NPY结合后YR的激活机制提供了分子见解。
