小柯机器人

美国北卡罗来纳大学教堂山分校Bryan L. Roth等研究人员合作揭示人类痒觉GPCR的结构、功能和药理学。该研究于2021年11月17日在线发表于国际一流学术期刊《自然》。

研究人员报道了MRGPRX2与Gi₁和G_q结合为三元复合物的激动剂稳定结构，并且其分别与内源性肽cortistatin-14和合成激动剂探针结合，以及MRGPRX2的有效拮抗剂探针的开发。研究人员还报道了一种特异性的MRGPRX4激动剂以及这种激动剂与MRGPRX4和G_q复合物的结构。这些发现有望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症的药物。

据悉，MRGPRX受体家族（MRGPRX1-4）是一个相对近期进化的，且与mas相关的G-蛋白偶联受体家族。其中，MRGPRX2和MRGPRX4是瘙痒和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G_i和G_q结合。

附：英文原文

Title: Structure, function and pharmacology of human itch GPCRs

Author: Cao, Can, Kang, Hye Jin, Singh, Isha, Chen, He, Zhang, Chengwei, Ye, Wenlei, Hayes, Byron W., Liu, Jing, Gumpper, Ryan H., Bender, Brian J., Slocum, Samuel T., Krumm, Brian E., Lansu, Katherine, McCorvy, John D., Kroeze, Wesley K., English, Justin G., DiBerto, Jeffrey F., Olsen, Reid H. J., Huang, Xi-Ping, Zhang, Shicheng, Liu, Yongfeng, Kim, Kuglae, Karpiak, Joel, Jan, Lily Y., Abraham, Soman N., Jin, Jian, Shoichet, Brian K., Fay, Jonathan F., Roth, Bryan L.

Issue&Volume: 2021-11-17

Abstract: The MRGPRX family of receptors (MRGPRX1–4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently1. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions2,3,4,5. MRGPRX2 couples to both Gi and Gq in mast cells6. Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq in ternary complexes 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 therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.

DOI: 10.1038/s41586-021-04126-6

Source: https://www.nature.com/articles/s41586-021-04126-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html