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<p>The κ-opioid receptor (KOR) is a member of the G protein-coupled receptor (GPCR) family, modulating cellular responses through transducers such as G proteins and β-arrestins. G-protein-biased KOR agonists aim to retain analgesic and antipruritic actions while limiting aversion and sedation. Aiming to inform G-biased KOR agonist design, we analyze signaling-relevant residues from structural and dynamic views. Here we show, using multiple complementary methods, shared residues that determine β-arrestin recruitment by nalfurafine and U-50,488H. Cryo-electron microscopy structures of the KOR-G<sub>i</sub> signaling complexes identify the ligand binding mode in the activated state. Vibrational spectroscopy reveals ligand-induced conformational changes. Cell-based mutant experiments pinpoint four amino acids (K227<sup>5.40</sup>, C286<sup>6.47</sup>, H291<sup>6.52</sup>, and Y312<sup>7.34</sup>; Ballesteros–Weinstein numbering is shown in superscript) that play crucial roles in β-arrestin recruitment. Furthermore, MD simulations revealed that the four mutants tend to adopt conformations with reduced β-arrestin recruitment activity. Our research findings provide a foundation for enhancing KOR-mediated therapeutic effects while minimizing unwanted side effects by targeting specific residues within the KOR ligand-binding pocket, including K227<sup>5.40</sup> and Y312<sup>7.34</sup>, which have previously been implicated in biased signaling.</p>

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Structural and dynamic insights into the biased signaling mechanism of the human kappa opioid receptor

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月28日

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  • Chiyo Suno-Ikeda,
  • Ryo Nishikawa,
  • Riko Suzuki,
  • Shun Yokoi,
  • Seiya Iwata,
  • Tomoyo Takai,
  • Takaya Ogura,
  • Mika Hirose,
  • Akihisa Tokuda,
  • Risako Katamoto,
  • Akitoshi Inoue,
  • Eri Asai,
  • Ryoji Kise,
  • Yukihiko Sugita,
  • Takayuki Kato,
  • Hiroshi Nagase,
  • Ayori Mitsutake,
  • Tsuyoshi Saitoh,
  • Kota Katayama,
  • Asuka Inoue,
  • Hideki Kandori,
  • Takuya Kobayashi,
  • Ryoji Suno

摘要

The κ-opioid receptor (KOR) is a member of the G protein-coupled receptor (GPCR) family, modulating cellular responses through transducers such as G proteins and β-arrestins. G-protein-biased KOR agonists aim to retain analgesic and antipruritic actions while limiting aversion and sedation. Aiming to inform G-biased KOR agonist design, we analyze signaling-relevant residues from structural and dynamic views. Here we show, using multiple complementary methods, shared residues that determine β-arrestin recruitment by nalfurafine and U-50,488H. Cryo-electron microscopy structures of the KOR-Gi signaling complexes identify the ligand binding mode in the activated state. Vibrational spectroscopy reveals ligand-induced conformational changes. Cell-based mutant experiments pinpoint four amino acids (K2275.40, C2866.47, H2916.52, and Y3127.34; Ballesteros–Weinstein numbering is shown in superscript) that play crucial roles in β-arrestin recruitment. Furthermore, MD simulations revealed that the four mutants tend to adopt conformations with reduced β-arrestin recruitment activity. Our research findings provide a foundation for enhancing KOR-mediated therapeutic effects while minimizing unwanted side effects by targeting specific residues within the KOR ligand-binding pocket, including K2275.40 and Y3127.34, which have previously been implicated in biased signaling.