2026-05-28 合肥物質科学研究院（HFIPS）
Beta01 achieves G protein biased activation by remodeling the intracellular conformation of KOR. (Image by ZHU Qingjun)
＜関連情報＞
- https://english.hf.cas.cn/nr/bth/202605/t20260528_1160009.html
- https://www.nature.com/articles/s41467-026-71455-3
β-アレスチンシグナル伝達を減弱させたカッパオピオイド受容体ペプチド作動薬の合理的設計 Rational design of a Kappa opioid receptor peptide agonist with attenuated β-arrestin signaling
Huanhuan Zhang,Ruolan Wang,Pan Shi,Gaoming Wang,Qingjun Zhu,Xinheng He,Youwei Xu,Qingning Yuan,Wen Hu,Kai Wu,Yong Zheng,Li Zhou,Jun Liang,Pei Lv,Ziyan Xu,Fan Yang,Yingbin Liu,Youwen Zhuang,H. Eric Xu,Yue Wang & Changlin Tian
Nature Communications Published:14 April 2026
DOI:https://doi.org/10.1038/s41467-026-71455-3 Unedited version
Abstract
Difelikefalin is an FDA-approved κ-opioid receptor (KOR) peptide agonist used to treat chronic pruritus. However, as a balanced agonist that activates both G protein and β-arrestin pathways, difelikefalin remains associated with undesirable side effects linked to β-arrestin signaling. Here, we report the cryo-EM structure of the difelikefalin-KOR-Gi complex, identifying Y3207.43 as a key residue that is critical for signaling bias. Guided by this structural insight, we engineer beta01, a β-amino acid-substituted analog with potent G protein activation but minimal β-arrestin recruitment. In mouse models, beta01 retains robust antinociceptive and antipruritic efficacy while significantly reducing sedation and anxiety-like behaviors. Structural, molecular dynamics simulations and 2D 13C-Met NMR analyses further reveal beta01 stabilizes a unique KOR conformation with an expanded intracellular cavity that disfavors β-arrestin binding. This work establishes a rational structure-based framework for designing safer and more effective GPCR-targeted therapeutics.
