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Updated: Jun 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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Structural insights into CXCR4 modulation and oligomerization.

Kei Saotome1, Luke L McGoldrick2, Jo-Hao Ho3

  • 1Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA. kei.saotome@regeneron.com.

Nature Structural & Molecular Biology
|September 23, 2024
PubMed
Summary
This summary is machine-generated.

Chemokine receptor CXCR4 activation by CXCL12 is detailed using cryo-EM. Structures reveal antagonist AMD3100 and antibody REGN7663 binding, plus CXCR4 oligomerization influencing function.

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Area of Science:

  • Structural Biology
  • Molecular Pharmacology
  • Cellular Signaling

Background:

  • The chemokine receptor CXCR4 (C-X-C chemokine receptor type 4) plays a critical role in various cellular processes.
  • Previous structural studies revealed an inactive, homodimeric form of CXCR4, leaving many regulatory aspects poorly understood.

Purpose of the Study:

  • To investigate the structural mechanisms of human CXCR4 regulation using cryo-electron microscopy.
  • To elucidate the binding modes of the ligand CXCL12, antagonist AMD3100, and antibody REGN7663.
  • To explore the structural basis of CXCR4 oligomerization and its functional implications.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to determine high-resolution structures of CXCR4.
  • Analysis of ligand-bound and oligomeric states of the receptor.

Main Results:

  • The chemokine CXCL12 (C-X-C motif chemokine ligand 12) activates CXCR4 by inserting its N-terminus into the orthosteric pocket.
  • The antagonist AMD3100 binds via electrostatic interactions with acidic residues within the receptor's transmembrane bundle.
  • The antibody REGN7663 binds to the extracellular face and inserts into the orthosteric pocket.
  • Cryo-EM revealed trimeric and tetrameric assemblies of CXCR4, demonstrating distinct subunit conformations.

Conclusions:

  • CXCR4 structure and function are regulated by ligand binding, antagonists, and antibodies.
  • Oligomerization of CXCR4 into trimeric and tetrameric forms influences receptor conformation and function, suggesting allosteric regulation.
  • These findings provide critical insights into chemokine receptor structural biology and potential therapeutic targeting.