8KEX

CryoEM structure of Gq coupled MRGPRX4 with agonist DCA-3P, local

Summary for 8KEX

• Entry DOI: 10.2210/pdb8kex/pdb
• EMDB information: 37191
• Descriptor: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4,Green fluorescent protein, (4~{R})-4-[(3~{R},5~{R},8~{R},9~{S},10~{S},12~{S},13~{R},14~{S},17~{R})-10,13-dimethyl-12-oxidanyl-3-phosphonooxy-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1~{H}-cyclopenta[a]phenanthren-17-yl]pentanoic acid (2 entities in total)
• Functional Keywords: mrgprx4, bile acid, cholestatic itch, gpcr, agonist, membrane protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 1
• Total formula weight: 80268.23

Authors

Yang, J.,Fan, J.P.,Lei, X.G. (deposition date: 2023-08-14, release date: 2024-11-06, Last modification date: 2024-12-25)

Primary citation

Yang, J.,Zhao, T.,Fan, J.,Zou, H.,Lan, G.,Guo, F.,Shi, Y.,Ke, H.,Yu, H.,Yue, Z.,Wang, X.,Bai, Y.,Li, S.,Liu, Y.,Wang, X.,Chen, Y.,Li, Y.,Lei, X.
Structure-guided discovery of bile acid derivatives for treating liver diseases without causing itch.
Cell, 187:7164-7182.e18, 2024

PubMed Abstract: Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects.

PubMed: 39476841
DOI: 10.1016/j.cell.2024.10.001

Experimental method

ELECTRON MICROSCOPY (3.2 Å)