Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Nat Chem Biol. 2023 Apr;19(4):416-422. doi: 10.1038/s41589-022-01173-6. Epub 2022 Oct 27.
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.
人类 MAS 相关 G 蛋白偶联受体 X1（MRGPRX1）优先表达于小直径初级感觉神经元，并参与痛觉和瘙痒的介导。内源性阿片肽片段 BAM8-22 和其正变构调节剂 ML382 对 MRGPRX1 的中枢激活已被证明可有效抑制持续性疼痛，使 MRGPRX1 成为非阿片类疼痛治疗的有前途的靶点。然而，MRGPRX1 的激活机制在很大程度上仍不清楚。在这里，我们报告了三种高分辨率冷冻电镜结构，分别为单独结合 BAM8-22 的 MRGPRX1-Gαq、同时结合 BAM8-22 和 ML382 的 MRGPRX1-Gαq 以及一种合成激动剂化合物-16。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。总之，我们的发现为 MRGPRX1 受体的激活和变构调节提供了分子理解，这可能有助于基于结构的非阿片类止痛药的设计。
