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<p>G-protein-coupled receptors (GPCRs) are significant signal transducers that exist as monomers and in multiple oligomeric forms. However, molecular mechanism driving their dynamic interconversion to regulate intricate signaling in class A GPCRs remains elusive, compounding our understanding of their related pathophysiological functions. Here, we present a set of 12 assemblies of the apelin receptor (APLNR), including dimeric apo state, agonistic small molecule- or nanobody-bound state of monomeric and dimeric APLNR with and without G-proteins, providing a detailed dynamic view of the monomer-dimer transition. High-resolution cryo-EM structures reveal that different ligands induce varying degrees of pre-dissociation of dimers in the absence of G-protein, with G-protein coupling facilitating the transition from dimeric to monomeric receptor. These insights enhance our understanding of the dynamic regulation of class A GPCRs between monomeric and dimeric forms and advance the rational drug design strategies aimed at selectively modulating of APLNR signaling.</p>

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Dynamic monomer-dimer transition in ligand-induced apelin receptor activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月3日

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  • Su-Yu Ji,
  • Wei-Wei Wang,
  • Yixin Yang,
  • Ping Xu,
  • Jiangrong Zhang,
  • Xinyue Zhao,
  • Kun Xi,
  • Shao-Kun Zang,
  • Dan-Dan Shen,
  • Chunyou Mao,
  • Qingya Shen,
  • Yan Zhang

摘要

G-protein-coupled receptors (GPCRs) are significant signal transducers that exist as monomers and in multiple oligomeric forms. However, molecular mechanism driving their dynamic interconversion to regulate intricate signaling in class A GPCRs remains elusive, compounding our understanding of their related pathophysiological functions. Here, we present a set of 12 assemblies of the apelin receptor (APLNR), including dimeric apo state, agonistic small molecule- or nanobody-bound state of monomeric and dimeric APLNR with and without G-proteins, providing a detailed dynamic view of the monomer-dimer transition. High-resolution cryo-EM structures reveal that different ligands induce varying degrees of pre-dissociation of dimers in the absence of G-protein, with G-protein coupling facilitating the transition from dimeric to monomeric receptor. These insights enhance our understanding of the dynamic regulation of class A GPCRs between monomeric and dimeric forms and advance the rational drug design strategies aimed at selectively modulating of APLNR signaling.