8K6M

Structural complex of neuropeptide Y receptor 1

Summary for 8K6M

• Entry DOI: 10.2210/pdb8k6m/pdb
• EMDB information: 36923
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-2, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: neuropeptide y receptor 1, complex, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 161004.79

Authors

Shen, S.Y.,Zhao, C.,Shao, Z.H. (deposition date: 2023-07-25, release date: 2024-07-31, Last modification date: 2025-07-02)

Primary citation

Shen, S.,Deng, Y.,Shen, C.,Chen, H.,Cheng, L.,Wu, C.,Zhao, C.,Yang, Z.,Hou, H.,Wang, K.,Shao, Z.,Deng, C.,Ye, F.,Yan, W.
Structural basis of neuropeptide Y signaling through Y 1 and Y 2 receptors.
MedComm (2020), 5:e565-e565, 2024

PubMed Abstract: Neuropeptide Y (NPY), a 36-amino-acid peptide, functions as a neurotransmitter in both the central and peripheral nervous systems by activating the NPY receptor subfamily. Notably, NPY analogs display varying selectivity and exert diverse physiological effects through their interactions with this receptor family. [Pro]-NPY and [Leu, Pro]-NPY, mainly acting on YR, reportedly increases blood pressure and postsynaptically potentiates the effect of other vasoactive substances above all, while N-terminal cleaved NPY variants in human body primary mediates angiogenesis and neurotransmitter release inhibition through YR. However, the recognition mechanisms of YR and YR with specific agonists remain elusive, thereby hindering subtype receptor-selective drug development. In this study, we report three cryo-electron microscopy (cryo-EM) structures of Gi2-coupled YR and YR in complexes with NPY, as well as YR bound to a selective agonist [Leu, Pro]-NPY. Combined with cell-based assays, our study not only reveals the conserved peptide-binding mode of NPY receptors but also identifies an additional sub-pocket that confers ligand selectivity. Moreover, our analysis of YR evolutionary dynamics suggests that this sub-pocket has undergone functional adaptive evolution across different species. Collectively, our findings shed light on the molecular underpinnings of neuropeptide recognition and receptor activation, and they present a promising avenue for the design of selective drugs targeting the NPY receptor family.

PubMed: 38882210
DOI: 10.1002/mco2.565

Experimental method

ELECTRON MICROSCOPY (3.3 Å)