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Updated: May 26, 2025

Author Spotlight: Exploring Cellular Processes by Modeling Ligands in Cryo-EM Maps
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Author Spotlight: Exploring Cellular Processes by Modeling Ligands in Cryo-EM Maps

Published on: July 19, 2024

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

Chongzhao You1, Mengting Jiang2, Tianyu Gao3

  • 1The 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.

Cell Reports
|February 23, 2025
PubMed

Insights

Structural insights into the motilin receptor (MTLR) reveal distinct binding mechanisms for agonists like azithromycin and DS-3801b. These findings guide the development of novel gastrointestinal prokinetic drugs.

Area of Science:

  • Structural Biology
  • Pharmacology
  • Gastroenterology

Background:

  • The motilin receptor (MTLR) is a therapeutic target for gastrointestinal (GI) disorders, including gastroparesis.
  • Developing effective MTLR agonists is hindered by drug tolerance and signaling bias.
  • Understanding MTLR ligand interactions is crucial for designing improved prokinetic agents.

Purpose of the Study:

  • To elucidate the structural basis of ligand recognition and signaling selectivity at the MTLR.
  • To provide insights for the rational design of next-generation GI prokinetic drugs.

Main Methods:

  • Cryoelectron microscopy (cryo-EM) was employed to determine the structures of MTLR bound to azithromycin and DS-3801b.
  • Analysis of ligand-receptor interactions and key structural motifs involved in signaling.

Main Results:

  • Distinct binding modes were observed for the macrolide azithromycin (deep orthosteric pocket) and the non-macrolide DS-3801b (clamp-like conformation).
  • Extracellular loop 2 (ECL2) plays a critical role in determining ligand specificity and modulating G-protein and β-arrestin signaling.
  • The "D2.60R2.63S3.28" motif and TM6/7 interactions are identified as key determinants of signaling selectivity.

Conclusions:

  • The study reveals novel structural mechanisms of MTLR activation by different agonists.
  • These findings provide a structural foundation for designing MTLR-targeting drugs with improved efficacy and safety profiles for GI motility disorders.
Keywords:
CP: Molecular biologyDS-3801bGPCRazithromycinbiased signalingmacrolide antibioticsmotilin receptorstructural biology

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