2. Academic Validation
  3. Decoding the structural basis of ligand recognition and biased signaling in the motilin receptor

Decoding the structural basis of ligand recognition and biased signaling in the motilin receptor

  • Cell Rep. 2025 Mar 25;44(3):115329. doi: 10.1016/j.celrep.2025.115329.
Chongzhao You 1,  Mengting Jiang 2,  Tianyu Gao 3,  Zining Zhu 4,  Xinheng He 5,  Youwei Xu 5,  Yuan Gao 5,  Yi Jiang 6,  H Eric Xu 7
Affiliations

Affiliations

  • 1 The 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. Electronic address: youchongzhao@gmail.com.
  • 2 Lingang Laboratory, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 3 The 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, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China.
  • 5 The 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.
  • 6 Lingang Laboratory, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: yjiang@lglab.ac.cn.
  • 7 The 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. Electronic address: eric.xu@simm.ac.cn.
PMID: 39987561 DOI: 10.1016/j.celrep.2025.115329
Abstract

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.

Keywords

CP: Molecular biology; DS-3801b; GPCR; azithromycin; biased signaling; macrolide antibiotics; motilin receptor; structural biology.

Figures
Products