Decoding the structural basis of ligand recognition and biased signaling in the motilin receptor
Summary: The motilin receptor (MTLR) is a key target for treating gastrointestinal (GI) disorders like gastroparesis, yet developing effective agonists remains challenging due to drug tolerance and signaling bias. We present cryoelectron microscopy (cryo-EM) structures of MTLR bound to azithromycin,...
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| Language: | English |
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Elsevier
2025-03-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725001007 |
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| author | Chongzhao You Mengting Jiang Tianyu Gao Zining Zhu Xinheng He Youwei Xu Yuan Gao Yi Jiang H. Eric Xu |
| author_facet | Chongzhao You Mengting Jiang Tianyu Gao Zining Zhu Xinheng He Youwei Xu Yuan Gao Yi Jiang H. Eric Xu |
| author_sort | Chongzhao You |
| collection | DOAJ |
| description | Summary: The motilin receptor (MTLR) is a key target for treating gastrointestinal (GI) disorders like gastroparesis, yet developing effective agonists remains challenging due to drug tolerance and signaling bias. We present cryoelectron microscopy (cryo-EM) structures of MTLR bound to azithromycin, a macrolide antibiotic, and DS-3801b, a non-macrolide agonist. Distinct ligand recognition mechanisms are revealed, with azithromycin binding deeply within the orthosteric pocket and DS-3801b adopting a special clamp-like conformation stabilized by a water molecule. We also highlight the critical role of extracellular loop 2 (ECL2) in ligand specificity and signaling pathway activation, affecting both G-protein and β-arrestin signaling. Additionally, the “D2.60R2.63S3.28” motif and interactions around transmembranes 6/7 (TM6/7) are identified as key drivers of signaling selectivity. These findings offer insights into the structural dynamics of MTLR, laying the groundwork for the rational design of next-generation GI prokinetic drugs with enhanced efficacy and safety. |
| format | Article |
| id | doaj-art-e31d576e881c4e92a4679129c372cd5a |
| institution | DOAJ |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-e31d576e881c4e92a4679129c372cd5a2025-08-20T02:45:07ZengElsevierCell Reports2211-12472025-03-0144311532910.1016/j.celrep.2025.115329Decoding the structural basis of ligand recognition and biased signaling in the motilin receptorChongzhao You0Mengting Jiang1Tianyu Gao2Zining Zhu3Xinheng He4Youwei Xu5Yuan Gao6Yi Jiang7H. Eric Xu8The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Corresponding authorLingang Laboratory, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaThe State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, ChinaThe State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaThe State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaThe State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaLingang Laboratory, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Corresponding authorThe State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Lingang Laboratory, Shanghai 200031, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Corresponding authorSummary: The motilin receptor (MTLR) is a key target for treating gastrointestinal (GI) disorders like gastroparesis, yet developing effective agonists remains challenging due to drug tolerance and signaling bias. We present cryoelectron microscopy (cryo-EM) structures of MTLR bound to azithromycin, a macrolide antibiotic, and DS-3801b, a non-macrolide agonist. Distinct ligand recognition mechanisms are revealed, with azithromycin binding deeply within the orthosteric pocket and DS-3801b adopting a special clamp-like conformation stabilized by a water molecule. We also highlight the critical role of extracellular loop 2 (ECL2) in ligand specificity and signaling pathway activation, affecting both G-protein and β-arrestin signaling. Additionally, the “D2.60R2.63S3.28” motif and interactions around transmembranes 6/7 (TM6/7) are identified as key drivers of signaling selectivity. These findings offer insights into the structural dynamics of MTLR, laying the groundwork for the rational design of next-generation GI prokinetic drugs with enhanced efficacy and safety.http://www.sciencedirect.com/science/article/pii/S2211124725001007CP: Molecular biology |
| spellingShingle | Chongzhao You Mengting Jiang Tianyu Gao Zining Zhu Xinheng He Youwei Xu Yuan Gao Yi Jiang H. Eric Xu Decoding the structural basis of ligand recognition and biased signaling in the motilin receptor Cell Reports CP: Molecular biology |
| title | Decoding the structural basis of ligand recognition and biased signaling in the motilin receptor |
| title_full | Decoding the structural basis of ligand recognition and biased signaling in the motilin receptor |
| title_fullStr | Decoding the structural basis of ligand recognition and biased signaling in the motilin receptor |
| title_full_unstemmed | Decoding the structural basis of ligand recognition and biased signaling in the motilin receptor |
| title_short | Decoding the structural basis of ligand recognition and biased signaling in the motilin receptor |
| title_sort | decoding the structural basis of ligand recognition and biased signaling in the motilin receptor |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725001007 |
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