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Structure paper

タイトル	Structure, function and pharmacology of human itch GPCRs.
ジャーナル・号・ページ	Nature, Vol. 600, Issue 7887, Page 170-175, Year 2021
掲載日	2021年11月17日
著者	Can Cao / Hye Jin Kang / Isha Singh / He Chen / Chengwei Zhang / Wenlei Ye / Byron W Hayes / Jing Liu / Ryan H Gumpper / Brian J Bender / Samuel T Slocum / Brian E Krumm / Katherine Lansu / John D McCorvy / Wesley K Kroeze / Justin G English / Jeffrey F DiBerto / Reid H J Olsen / Xi-Ping Huang / Shicheng Zhang / Yongfeng Liu / Kuglae Kim / Joel Karpiak / Lily Y Jan / Soman N Abraham / Jian Jin / Brian K Shoichet / Jonathan F Fay / Bryan L Roth /
PubMed 要旨	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 ...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 G and G in mast cells. Here we describe agonist-stabilized structures of MRGPRX2 coupled to G and G 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 G. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.
リンク	Nature / PubMed:34789874 / PubMed Central
手法	EM (単粒子)
解像度	2.45 - 2.9 Å
構造データ	24896 7s8l EMDB-24896, PDB-7s8l: CryoEM structure of Gq-coupled MRGPRX2 with peptide agonist Cortistatin-14 手法: EM (単粒子) / 解像度: 2.45 Å 24897 7s8m EMDB-24897, PDB-7s8m: CryoEM structure of Gi-coupled MRGPRX2 with peptide agonist Cortistatin-14 手法: EM (単粒子) / 解像度: 2.54 Å 24898 7s8n EMDB-24898, PDB-7s8n: CryoEM structure of Gq-coupled MRGPRX2 with small molecule agonist (R)-Zinc-3573 手法: EM (単粒子) / 解像度: 2.9 Å 24899 7s8o EMDB-24899, PDB-7s8o: CryoEM structure of Gi-coupled MRGPRX2 with small molecule agonist (R)-Zinc-3573 手法: EM (単粒子) / 解像度: 2.58 Å 24900 7s8p EMDB-24900, PDB-7s8p: CryoEM structure of Gq-coupled MRGPRX4 with small molecule agonist MS47134 手法: EM (単粒子) / 解像度: 2.6 Å
化合物	ChemComp-8IU: (3R)-N,N-dimethyl-1-[(8S)-5-phenylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-amine / (R)-ZINC-3573 ChemComp-8IX: N-[(1r,3R,5S,7R)-3,5-dimethyltricyclo[3.3.1.1~3,7~]decane-1-carbonyl]-D-phenylalanine
由来	homo sapiens (ヒト) mus musculus (ハツカネズミ) escherichia coli (大腸菌)
キーワード	SIGNALING PROTEIN / GPCR (Gタンパク質共役受容体)