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- Title
Ligand recognition and activation of neuromedin U receptor 2.
- Authors
Zhao, Wenli; Zhang, Wenru; Wang, Mu; Lu, Minmin; Chen, Shutian; Tang, Tingting; Schnapp, Gisela; Wagner, Holger; Brennauer, Albert; Yi, Cuiying; Chu, Xiaojing; Han, Shuo; Wu, Beili; Zhao, Qiang
- 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. Neuromedin U receptor 2 is an emerging attractive target for treating obesity. Here, a Cryo-EM structure of NmU-25–NMU2–Gi1 provides the structural basis for the designation of highly selective drugs.
- Subjects
G protein coupled receptors; PEPTIDES; G proteins; DRUG development; ENERGY metabolism; FOOD consumption
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-34814-4