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Cell reports

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

Published:25 March 2025 DOI: 10.1016/j.celrep.2025.115329 PMID: 39987561
Chongzhao You,?Mengting Jiang,?Tianyu Gao,?Zining Zhu,?Xinheng He,?Youwei Xu,?Yuan Gao,?Yi Jiang,?H Eric Xu

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.

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