Ligand recognition and activation of neuromedin U receptor 2

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 () and Qiang Zhao ()
Additional contact information
Wenli Zhao: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Wenru Zhang: Nanjing University of Chinese Medicine
Mu Wang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Minmin Lu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Shutian Chen: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Tingting Tang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Gisela Schnapp: Boehringer-Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry
Holger Wagner: Boehringer-Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry
Albert Brennauer: Boehringer-Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry
Cuiying Yi: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Xiaojing Chu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Shuo Han: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Beili Wu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Qiang Zhao: Shanghai Institute of Materia Medica, Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34814-4

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