Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists
Top Cited Papers
- 19 November 2010
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 330 (6007) , 1066-1071
- https://doi.org/10.1126/science.1194396
Abstract
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 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.This publication has 72 references indexed in Scilit:
- Structure of a clade C HIV-1 gp120 bound to CD4 and CD4-induced antibody reveals anti-CD4 polyreactivityNature Structural & Molecular Biology, 2010
- Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobilityProceedings of the National Academy of Sciences, 2009
- Conserved waters mediate structural and functional activation of family A (rhodopsin-like) G protein-coupled receptorsProceedings of the National Academy of Sciences, 2009
- Increasingly accurate dynamic molecular models of G-protein coupled receptor oligomers: Panacea or Pandora's box for novel drug discovery?Life Sciences, 2009
- Modulation of chemokine receptor activity through dimerization and crosstalkCellular and Molecular Life Sciences, 2008
- Molecular architecture of native HIV-1 gp120 trimersNature, 2008
- Structure of a β1-adrenergic G-protein-coupled receptorNature, 2008
- A Specific Cholesterol Binding Site Is Established by the 2.8 Å Structure of the Human β2-Adrenergic ReceptorStructure, 2008
- Stabilization of the Human β2-Adrenergic Receptor TM4–TM3–TM5 Helix Interface by Mutagenesis of Glu1223.41, A Critical Residue in GPCR StructureJournal of Molecular Biology, 2007
- Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar developmentNature, 1998