Research Article

Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists

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Science  07 Oct 2010:
DOI: 10.1126/science.1194396


Chemokine receptors are critical regulators of cell migration in the context of immune surveillance, inflammation, and development. The G protein–coupled chemokine receptor, CXCR4, is specifically implicated in cancer metastasis and HIV-1 infection. Here, we report five independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5 to 3.2 angstrom resolution. All structures reveal a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling. The location and shape of the ligand-binding sites differ from other G protein–coupled receptors (GPCRs) and are closer to the extracellular surface. These structures provide new clues about the interactions between CXCR4 and its natural ligand CXCL12 and with the HIV-1 glycoprotein gp120.