Structure of the human k-opioid receptor in complex with JDTic
Structure of the human k-opioid receptor in complex with JDTic
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发表时间：
2012
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通讯作者：
Hui-Lin Wu;Daniel Wacker;Mauro Mileni;V. Katritch;Gye Won Han;Eyal Vardy;Wei Liu;Aaron A. Thompson-Aaron-A.-Th
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作者：
Hui-Lin Wu;Daniel Wacker;Mauro Mileni;V. Katritch;Gye Won Han;Eyal Vardy;Wei Liu;Aaron A. Thompson-Aaron-A.-Th
阿片受体介导内源性和外源性阿片对许多生理过程的作用，包括疼痛、呼吸驱动、情绪的调节，以及在k-阿片受体（k-OR）的情况下的烦躁和拟精神病。在这里，我们报告的晶体结构的人k-OR在复杂的选择性拮抗剂JDTic，安排在平行的二聚体，在2.9 μ m分辨率。该结构揭示了配体结合口袋的重要特征，这些特征有助于JDTic对人k-OR的高亲和力和亚型选择性。其他重要的k-OR-选择性配体，包括吗啡衍生的拮抗剂norbinaltorphimine和59-guanidinonaltrindole，和二萜激动剂鼠尾草素A类似物RB-64的建模，揭示了结合这些不同的化学型的共同和独特的功能。定点诱变和配体结构-活性关系的分析证实了在晶体结构中观察到的相互作用，从而为k-OR亚型选择性提供了分子解释，并为设计具有靶向人k-OR的新药理学性质的化合物提供了重要见解。
Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and—in the case of k-opioid receptor (k-OR)—dysphoria and psychotomimesis. Here we report the crystal structure of the human k-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 Å resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human k-OR. Modelling of other important k-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 59-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure–activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for k-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human k-OR.