| Literature DB >> 34789874 |
Can Cao1, Hye Jin Kang1, Isha Singh2, He Chen3, Chengwei Zhang3, Wenlei Ye4, Byron W Hayes5, Jing Liu3, Ryan H Gumpper1, Brian J Bender2, Samuel T Slocum1, Brian E Krumm1, Katherine Lansu1, John D McCorvy1,6, Wesley K Kroeze1, Justin G English1,7, Jeffrey F DiBerto1, Reid H J Olsen1, Xi-Ping Huang1, Shicheng Zhang1, Yongfeng Liu1, Kuglae Kim1, Joel Karpiak2, Lily Y Jan4,8, Soman N Abraham5,9, Jian Jin3, Brian K Shoichet10, Jonathan F Fay11, Bryan L Roth12.
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 reactions2-5. 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.Entities:
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Year: 2021 PMID： 34789874 PMCID： PMC9150435 DOI： 10.1038/s41586-021-04126-6
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 69.504