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Science 330 (6007): 1066-1071

Copyright © 2010 by the American Association for the Advancement of Science

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

Beili Wu,1 Ellen Y. T. Chien,1 Clifford D. Mol,1 Gustavo Fenalti,1 Wei Liu,1 Vsevolod Katritch,2 Ruben Abagyan,2 Alexei Brooun,3 Peter Wells,3 F. Christopher Bi,3 Damon J. Hamel,2 Peter Kuhn,1 Tracy M. Handel,2 Vadim Cherezov,1 Raymond C. Stevens1,*

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.

1 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA 92093, USA.
3 Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA.

* To whom correspondence should be addressed. E-mail: stevens{at}

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J. Biol. Chem. 286, 31661-31675
   Abstract »    Full Text »    PDF »
Molecular Basis of Secretin Docking to Its Intact Receptor Using Multiple Photolabile Probes Distributed throughout the Pharmacophore.
M. Dong, P. C.- H. Lam, D. I. Pinon, K. Hosohata, A. Orry, P. M. Sexton, R. Abagyan, and L. J. Miller (2011)
J. Biol. Chem. 286, 23888-23899
   Abstract »    Full Text »    PDF »
Computational analysis of the structural mechanism of inhibition of chemokine receptor CXCR4 by small molecule antagonists.
S. P. Kawatkar, M. Yan, H. Gevariya, M. Y. Lim, S. Eisold, X. Zhu, Z. Huang, and J. An (2011)
Experimental Biology and Medicine 236, 844-850
   Abstract »    Full Text »    PDF »
Comparative Fluorescence Resonance Energy Transfer Analysis of Metabotropic Glutamate Receptors: IMPLICATIONS ABOUT THE DIMERIC ARRANGEMENT AND REARRANGEMENT UPON LIGAND BINDINGS.
M. Yanagawa, T. Yamashita, and Y. Shichida (2011)
J. Biol. Chem. 286, 22971-22981
   Abstract »    Full Text »    PDF »
Biology and clinical relevance of chemokines and chemokine receptors CXCR4 and CCR5 in human diseases.
W.-T. Choi and J. An (2011)
Experimental Biology and Medicine 236, 637-647
   Abstract »    Full Text »    PDF »
Lipid cubic phase as a membrane mimetic for integral membrane protein enzymes.
D. Li and M. Caffrey (2011)
PNAS 108, 8639-8644
   Abstract »    Full Text »    PDF »
Two distinct conformations of helix 6 observed in antagonist-bound structures of a {beta}1-adrenergic receptor.
R. Moukhametzianov, T. Warne, P. C. Edwards, M. J. Serrano-Vega, A. G. W. Leslie, C. G. Tate, and G. F. X. Schertler (2011)
PNAS 108, 8228-8232
   Abstract »    Full Text »    PDF »
New G-protein-coupled receptor structures provide insights into the recognition of CXCL12 and HIV-1 gp120 by CXCR4.
C. Zhong and J. Ding (2011)
Acta Biochim Biophys Sin 43, 337-338
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Structure of an Agonist-Bound Human A2A Adenosine Receptor.
F. Xu, H. Wu, V. Katritch, G. W. Han, K. A. Jacobson, Z.-G. Gao, V. Cherezov, and R. C. Stevens (2011)
Science 332, 322-327
   Abstract »    Full Text »    PDF »
Helix 8 of the M1 Muscarinic Acetylcholine Receptor: Scanning Mutagenesis Delineates a G Protein Recognition Site.
R. G. Kaye, J. W. Saldanha, Z.-L. Lu, and E. C. Hulme (2011)
Mol. Pharmacol. 79, 701-709
   Abstract »    Full Text »    PDF »
G Protein Activation by Serotonin Type 4 Receptor Dimers: EVIDENCE THAT TURNING ON TWO PROTOMERS IS MORE EFFICIENT.
L. P. Pellissier, G. Barthet, F. Gaven, E. Cassier, E. Trinquet, J.-P. Pin, P. Marin, A. Dumuis, J. Bockaert, J.-L. Baneres, et al. (2011)
J. Biol. Chem. 286, 9985-9997
   Abstract »    Full Text »    PDF »
Recognition in the Face of Diversity: Interactions of Heterotrimeric G proteins and G Protein-coupled Receptor (GPCR) Kinases with Activated GPCRs.
C.-c. Huang and J. J. G. Tesmer (2011)
J. Biol. Chem. 286, 7715-7721
   Abstract »    Full Text »    PDF »

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