纳米抗体稳定的κ阿片受体活性状态结构。
Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor.
机构信息
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Molecular Pharmacology Program and Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
出版信息
Cell. 2018 Jan 11;172(1-2):55-67.e15. doi: 10.1016/j.cell.2017.12.011. Epub 2018 Jan 4.
The κ-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric, and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here, we provide a crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody. Comparisons between inactive- and active-state opioid receptor structures reveal substantial conformational changes in the binding pocket and intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger-scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective κ-opioid receptor therapeutics.
κ 阿片受体（KOP）介导具有致幻、烦躁不安和镇痛作用的阿片类药物的作用。由于对 KOP 激动剂作用的结构和机制理解不完整，因此设计没有致幻和烦躁不安作用的 KOP 镇痛药受到了阻碍。在这里，我们提供了人 KOP 与强效环氧吗啡类阿片激动剂 MP1104 和一种活性状态稳定的纳米抗体复合物的晶体结构。与非活性状态和活性状态阿片受体结构的比较揭示了结合口袋以及细胞内和细胞外区域的显著构象变化。广泛的结构分析和实验验证阐明了关键残基，这些残基可以传播更大规模的结构重排和转导器结合，这些共同阐明了 KOP 药理学、功能和偏向信号传导的结构决定因素。这些分子见解有望加速更安全、更有效的 κ 阿片受体治疗药物的结构导向设计。
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