应用化学2026，Vol.43Issue(7)：1033-1050,中插1-中插19,37.DOI:10.19894/j.issn.1000-0518.260175
μ-阿片受体N端作为动态门控与N40D突变配体特异性的机制探讨
Mechanistic Exploration of N-Terminal Dynamic Gating in the μ-Opioid Receptor and Ligand Specificity of the N40D Mutation
摘要
Abstract
The A118G polymorphism(N40D substitution)in the OPRM1 gene presents a clinical paradox:it attenuates the analgesic efficacy of morphine while concomitantly heightening sensitivity to fentanyl.The underlying molecular mechanisms have remained elusive,partly because previous structural studies of the μ-opioid receptor(MOR)typically lacked the N-terminal sequence.Through microsecond molecular dynamics(MD)simulations of the intact-N-terminus MOR,we reveal that the dynamic N-terminus acts as an auto-inhibitory lid,imposing steric hindrance over the drug-binding pocket.Furthermore,a novel lateral entry pathway regulated by transmembrane helix 1(TM1)was identified.The findings indicate that while the N40D mutation thermodynamically facilitates MOR activation by disrupting this lid,the ligand-specific differences are primarily driven by binding kinetics:the mutation significantly reduces the residence time of morphine.In contrast,the dissociation of fentanyl is buffered by its membrane reservoir effect and efficient rebinding capacity.Synthesizing these findings,this study proposes a"lateral binding mechanism"model that incorporates N-terminal gating.This model helps elucidate the spatiotemporal sequence of initial ligand engagement with the MOR,offering a plausible molecular basis for the mutation-induced ligand-specific effects and providing new insights into the MOR activation process.关键词
μ-阿片受体/A118G多态性/分子动力学模拟/侧向结合路径/变构调节Key words
μ-opioid receptor/A118G polymorphism,Molecular dynamics simulation/Lateral binding pathway/Allosteric regulation分类
化学化工引用本文复制引用
蒋定军,杨月峰,王乙博,李鹏辉,王晓辉..μ-阿片受体N端作为动态门控与N40D突变配体特异性的机制探讨[J].应用化学,2026,43(7):1033-1050,中插1-中插19,37.基金项目
国家自然科学基金(Nos.82550005,T2350008)、脑科学与类脑研究国家科技重大专项(No.2021ZD0203000(2021ZD0303000))、中国科学院国际伙伴计划(No.029GJHZ2024057GC)和吉林省科技厅项目(No.20260101011JJ)资助 Supported by the National Natural Science Foundation of China(Nos.82550005,T2350008),the National Science and Technology Major Project on Brain Science and Brain-Inspired Research(Nos.2021ZD0203000(2021ZD0303000)),the International Partnership Program of the Chinese Academy of Sciences(No.029GJHZ2024057GC)and the Project of the Science and Technology Department of Jilin Province(No.20260101011JJ) （Nos.82550005,T2350008）
