Ligand recognition and activation of neuromedin U receptor 2.

Abstract

Neuromedin U receptor 2 (NMU2), an emerging attractive target for treating obesity, has shown the capability in reducing food intake and regulating energy metabolism when activated. However, drug development of NMU2 was deferred partially due to the lack of structural information. Here, we present the cryo-electron microscopy (cryo-EM) structure of NMU2 bound to the endogenous agonist NmU-25 and Gi1 at 3.3 Å resolution. Combined with functional and computational data, the structure reveals the key factors that govern the recognition and selectivity of peptide agonist as well as non-peptide antagonist, providing the structural basis for design of novel and highly selective drugs targeting NMU2. In addition, a 25-degree rotation of Gi protein in reference to NMU2 is also observed compared in other structures of class A GPCR-Gi complexes, suggesting heterogeneity in the processes of G protein-coupled receptors (GPCRs) activation and G protein coupling.

• Authors: Wenli Zhao, Wenru Zhang, Mu Wang, Minmin Lu, Shutian Chen, Tingting Tang, Gisela Schnapp, Holger Wagner, Albert Brennauer, Cuiying Yi, Xiaojing Chu, Shuo Han, Beili Wu, Qiang Zhao
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 7955 (12 27 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 36575163 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• neuromedin U receptor
• Ligands
• Receptors, G-Protein-Coupled
• Receptors, Neurotransmitter
• GTP-Binding Proteins

Topics

• Ligands
• Cryoelectron Microscopy
• Receptors, G-Protein-Coupled (metabolism)
• Receptors, Neurotransmitter (metabolism)
• GTP-Binding Proteins (metabolism)