8K4S

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

Summary for 8K4S

• Entry DOI: 10.2210/pdb8k4s/pdb
• EMDB information: 36890
• Descriptor: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4,Green fluorescent protein, Gs-mini-Gq chimera, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: mrgprx4, bile acid, cholestatic itch, gpcr, agonist, membrane protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 5
• Total formula weight: 181157.66

Authors

Yang, J.,Fan, J.P.,Lei, X.G. (deposition date: 2023-07-20, 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 (2.9 Å)