9JMD

Cryo-EM structure of the Azithromycin-Motilin receptor-Gq protein complex

Summary for 9JMD

• Entry DOI: 10.2210/pdb9jmd/pdb
• EMDB information: 61598
• Descriptor: Guanine nucleotide-binding protein G(q) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ScFv16, ... (8 entities in total)
• Functional Keywords: cryo-em, gpcr, motilin receptor, azithromycin, macrolide antibiotics, gq, complex, signaling protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 5
• Total formula weight: 160561.60

Authors

Xu, H.E.,You, C.,Jiang, Y. (deposition date: 2024-09-20, release date: 2025-05-28, Last modification date: 2025-06-25)

Primary citation

You, C.,Jiang, M.,Gao, T.,Zhu, Z.,He, X.,Xu, Y.,Gao, Y.,Jiang, Y.,Xu, H.E.
Decoding the structural basis of ligand recognition and biased signaling in the motilin receptor.
Cell Rep, 44:115329-115329, 2025

PubMed 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 "DRS" 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.

PubMed: 39987561
DOI: 10.1016/j.celrep.2025.115329

Experimental method

ELECTRON MICROSCOPY (2.74 Å)