2. Academic Validation
  3. Structural basis of neuropeptide Y signaling through Y1 receptor

Structural basis of neuropeptide Y signaling through Y1 receptor

  • Nat Commun. 2022 Feb 14;13(1):853. doi: 10.1038/s41467-022-28510-6.
Chaehee Park # 1,  Jinuk Kim # 1,  Seung-Bum Ko 1,  Yeol Kyo Choi 2,  Hyeongseop Jeong 3,  Hyeonuk Woo 4,  Hyunook Kang 1,  Injin Bang 1 5,  Sang Ah Kim 1 6,  Tae-Young Yoon 1 6,  Chaok Seok 4,  Wonpil Im 2,  Hee-Jung Choi 7
Affiliations

Affiliations

  • 1 Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
  • 2 Departments of Biological Sciences and Chemistry, Lehigh University, Bethlehem, PA, 18015, USA.
  • 3 Center for Electron Microscopy Research, Korea Basic Science Institute, Chungcheongbuk-do, 28119, Republic of Korea.
  • 4 Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea.
  • 5 Perlmutter Cancer Center, New York University Langone Health, and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, 10016, NY, USA.
  • 6 Institute for Molecular Biology and Genetics, Seoul National University, Seoul, 08826, Republic of Korea.
  • 7 Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea. choihj@snu.ac.kr.
  • # Contributed equally.
PMID: 35165283 DOI: 10.1038/s41467-022-28510-6
Abstract

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 (Y1R) in complex with Gi1 protein. The NPY C-terminal segment forming the extended conformation binds deep into the Y1R 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 Y1R extracellular loops, contributing to the high affinity of NPY for Y1R. The structural analysis of NPY-bound Y1R and mutagenesis studies provide molecular insights into the activation mechanism of Y1R upon NPY binding.

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