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Ligand recognition and allosteric modulation of the human MRGPRX1 receptor
Nature Chemical Biology ( IF 14.8 ) Pub Date : 2022-10-27 , DOI: 10.1038/s41589-022-01173-6
Yongfeng Liu 1, 2 , Can Cao 1 , Xi-Ping Huang 1, 2 , Ryan H Gumpper 1 , Moira M Rachman 3 , Sheng-Luen Shih 1, 2 , Brian E Krumm 1 , Shicheng Zhang 1 , Brian K Shoichet 3 , Jonathan F Fay 4, 5 , Bryan L Roth 1, 2, 6
Affiliation  

The human MAS-related G protein–coupled receptor X1 (MRGPRX1) is preferentially expressed in the small-diameter primary sensory neurons and involved in the mediation of nociception and pruritus. Central activation of MRGPRX1 by the endogenous opioid peptide fragment BAM8-22 and its positive allosteric modulator ML382 has been shown to effectively inhibit persistent pain, making MRGPRX1 a promising target for non-opioid pain treatment. However, the activation mechanism of MRGPRX1 is still largely unknown. Here we report three high-resolution cryogenic electron microscopy structures of MRGPRX1–Gαq in complex with BAM8-22 alone, with BAM8-22 and ML382 simultaneously as well as with a synthetic agonist compound-16. These structures reveal the agonist binding mode for MRGPRX1 and illuminate the structural requirements for positive allosteric modulation. Collectively, our findings provide a molecular understanding of the activation and allosteric modulation of the MRGPRX1 receptor, which could facilitate the structure-based design of non-opioid pain-relieving drugs.



中文翻译:

人 MRGPRX1 受体的配体识别和变构调节

人类 MAS 相关 G 蛋白偶联受体 X1 (MRGPRX1) 优先在小直径初级感觉神经元中表达,并参与伤害感受和瘙痒的介导。内源性阿片肽片段 BAM8-22 及其正变构调节剂 ML382 对 MRGPRX1 的中枢激活已被证明可以有效抑制持续性疼痛,使 MRGPRX1 成为非阿片类疼痛治疗的有希望的靶点。然而,MRGPRX1的激活机制仍然很大程度上未知。在这里,我们报告了 MRGPRX1-Gαq 与单独的 BAM8-22、同时与 BAM8-22 和 ML382 以及与合成激动剂化合物 16 复合的三种高分辨率低温电子显微镜结构。这些结构揭示了 MRGPRX1 的激动剂结合模式,并阐明了正变构调节的结构要求。总的来说,我们的研究结果提供了对 MRGPRX1 受体的激活和变构调节的分子理解,这可以促进非阿片类止痛药物的基于结构的设计。

更新日期:2022-10-28
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