Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists

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

Research output: Contribution to journalReview article

1235 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1066-1071
Number of pages6
JournalScience
Volume330
Issue number6007
DOIs
StatePublished - Nov 19 2010
Externally publishedYes

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Cyclic Peptides
Chemokine Receptors
G-Protein-Coupled Receptors
Chemokines
HIV-1
Ligands
HIV Infections
Cell Movement
Glycoproteins
Binding Sites
Neoplasm Metastasis
Inflammation
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Wu, B., Chien, E. Y. T., Mol, C. D., Fenalti, G., Liu, W., Katritch, V., ... Stevens, R. C. (2010). Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science, 330(6007), 1066-1071. https://doi.org/10.1126/science.1194396

Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. / Wu, Beili; Chien, Ellen Y.T.; Mol, Clifford D.; Fenalti, Gustavo; Liu, Wei; Katritch, Vsevolod; Abagyan, Ruben; Brooun, Alexei; Wells, Peter; Bi, F. Christopher; Hamel, Damon J.; Kuhn, Peter; Handel, Tracy M.; Cherezov, Vadim; Stevens, Raymond C.

In: Science, Vol. 330, No. 6007, 19.11.2010, p. 1066-1071.

Research output: Contribution to journalReview article

Wu, B, Chien, EYT, Mol, CD, Fenalti, G, Liu, W, Katritch, V, Abagyan, R, Brooun, A, Wells, P, Bi, FC, Hamel, DJ, Kuhn, P, Handel, TM, Cherezov, V & Stevens, RC 2010, 'Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists', Science, vol. 330, no. 6007, pp. 1066-1071. https://doi.org/10.1126/science.1194396
Wu, Beili ; Chien, Ellen Y.T. ; Mol, Clifford D. ; Fenalti, Gustavo ; Liu, Wei ; Katritch, Vsevolod ; Abagyan, Ruben ; Brooun, Alexei ; Wells, Peter ; Bi, F. Christopher ; Hamel, Damon J. ; Kuhn, Peter ; Handel, Tracy M. ; Cherezov, Vadim ; Stevens, Raymond C. / Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. In: Science. 2010 ; Vol. 330, No. 6007. pp. 1066-1071.
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AU - Liu, Wei

AU - Katritch, Vsevolod

AU - Abagyan, Ruben

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AU - Wells, Peter

AU - Bi, F. Christopher

AU - Hamel, Damon J.

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AU - Handel, Tracy M.

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AU - Stevens, Raymond C.

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AB - 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.

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