Structure, function and pharmacology of human itch GPCRs.
Structure, function and pharmacology of human itch GPCRs.
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DOI：
10.1038/s41586-021-04126-6
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发表时间：
2021-12
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
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作者：
MRGPRX受体家族(MRGPRX1-4)是近年来发展起来的一个与Mas相关的G蛋白偶联受体家族。其中，MRGPRX2和MRGPRX4是瘙痒及相关肥大细胞介导的超敏反应的关键生理和病理介质。MRGPRX2与肥大细胞中的GI和GQ偶联。在这里，我们描述了MRGPRX2与GI1和GQ偶联的激动剂稳定结构，分别与内源性多肽皮质酮-14和合成的激动剂探针形成三元复合体，以及MRGPRX2的有效拮抗探针的开发。我们还描述了一种特定的MRGPRX4激动剂以及该激动剂与MRGPRX4和GQ形成的复合体的结构。总而言之，这些发现应该会加速在结构指导下发现治疗疼痛、瘙痒和肥大细胞介导的超敏反应的药物。
The MRGPRX family of receptors (MRGPRX1-4) is a family of Mas-related G protein coupled receptors that have evolved relatively recently. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast-cell mediated hypersensitivity reactions. MRGPRX2 couples to both Gi and Gq in mast cells. Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq in ternary complex with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and Gq. Together, these findings should accelerate the structure-guided discovery of therapeutics for pain, itch and mast-cell mediated hypersensitivity.