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OA

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.