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TitleStructure-guided discovery of bile acid derivatives for treating liver diseases without causing itch.
Journal, issue, pagesCell, Vol. 187, Issue 25, Page 7164-7182.e18, Year 2024
Publish dateDec 12, 2024
AuthorsJun Yang / Tianjun Zhao / Junping Fan / Huaibin Zou / Guangyi Lan / Fusheng Guo / Yaocheng Shi / Han Ke / Huasheng Yu / Zongwei Yue / Xin Wang / Yingjie Bai / Shuai Li / Yingjun Liu / Xiaoming Wang / Yu Chen / Yulong Li / Xiaoguang Lei /
PubMed AbstractChronic 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 ...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.
External linksCell / PubMed:39476841
MethodsEM (single particle)
Resolution2.9 - 3.2 Å
Structure data

36890

8k4s

EMDB-36890, PDB-8k4s:
CryoEM structure of Gq coupled MRGPRX4 with agonist DCA-3P
Method: EM (single particle) / Resolution: 2.9 Å

37191

8kex

EMDB-37191, PDB-8kex:
CryoEM structure of Gq coupled MRGPRX4 with agonist DCA-3P, local
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals


ChemComp, No image

ChemComp-JW0:
Unknown entry

Source
  • homo sapiens (human)
  • aequorea victoria (jellyfish)
  • mus musculus (house mouse)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / MRGPRX4 / Bile acid / Cholestatic itch / GPCR / Agonist

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