Related Experiment Video

Updated: Aug 12, 2025

A Flow Cytometry-based Assay to Identify Compounds That Disrupt Binding of Fluorescently-labeled CXC Chemokine Ligand 12 to CXC Chemokine Receptor 4
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A Flow Cytometry-based Assay to Identify Compounds That Disrupt Binding of Fluorescently-labeled CXC Chemokine Ligand 12 to CXC Chemokine Receptor 4

Published on: March 10, 2018

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Internal water channel formation in CXCR4 is crucial for Gi-protein coupling upon activation by CXCL12

Chun-Chun Chang1,2, Je-Wen Liou3, Kingsley Theras Primus Dass4

  • 1Department of Laboratory Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 97004, Taiwan.

Communications Chemistry
|January 27, 2023
PubMed

Insights

Molecular dynamics simulations reveal how chemokine receptor CXCR4 activates. This study elucidates internal water channel formation in CXCR4, offering insights for anticancer drug development targeting cell migration.

Area of Science:

  • Structural Biology
  • Computational Biophysics
  • Molecular Pharmacology

Background:

  • Chemokine receptor CXCR4 plays a critical role in cell migration and development, making it a key target for various diseases.
  • Understanding the activation mechanism of CXCR4 is crucial for developing targeted therapeutics.

Purpose of the Study:

  • To determine the atomic-level activation mechanism of CXCR4 in complex with chemokine CXCL12 and G-protein.
  • To investigate the formation of internal water channels during CXCR4 activation.
  • To propose a model for CXCR4 activation relevant to drug development.

Main Methods:

  • Atomic-level molecular dynamics simulations were employed.
  • Simulations focused on the CXCR4 complex with CXCL12 and GDP-bound G-protein.

Main Results:

  • CXCL12-bound CXCR4 exhibited outward movement of transmembrane helix 6 (TM6) and altered tyrosine toggle switch dynamics.
  • A continuous internal water channel formed due to the breakage of a hydrophobic layer.
  • G-protein activation involved rotation and translation of its α5-helix, facilitating GDP release.

Conclusions:

  • A novel model for internal water channel formation during CXCL12-bound CXCR4 activation with G-protein was proposed.
  • This model provides valuable insights for the development of anticancer drugs targeting CXCR4.
  • The findings contribute to understanding GPCR activation and signaling pathways.

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