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

doi:10.1126/science.1194396

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 journal › Review article › peer-review

1515 Scopus citations

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 language	English (US)
Pages (from-to)	1066-1071
Number of pages	6
Journal	Science
Volume	330
Issue number	6007
DOIs	https://doi.org/10.1126/science.1194396
State	Published - Nov 19 2010
Externally published	Yes

ASJC Scopus subject areas

General

Access to Document

10.1126/science.1194396

Cite this

@article{6e694c59f7f544b98aed45359f324d8d,

title = "Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists",

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.",

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

year = "2010",

month = nov,

day = "19",

doi = "10.1126/science.1194396",

language = "English (US)",

volume = "330",

pages = "1066--1071",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6007",

}

TY - JOUR

T1 - Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists

AU - Wu, Beili

AU - Chien, Ellen Y.T.

AU - Mol, Clifford D.

AU - Fenalti, Gustavo

AU - Liu, Wei

AU - Katritch, Vsevolod

AU - Abagyan, Ruben

AU - Brooun, Alexei

AU - Wells, Peter

AU - Bi, F. Christopher

AU - Hamel, Damon J.

AU - Kuhn, Peter

AU - Handel, Tracy M.

AU - Cherezov, Vadim

AU - Stevens, Raymond C.

PY - 2010/11/19

Y1 - 2010/11/19

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85027927015&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027927015&partnerID=8YFLogxK

U2 - 10.1126/science.1194396

DO - 10.1126/science.1194396

M3 - Review article

AN - SCOPUS:85027927015

SN - 0036-8075

VL - 330

SP - 1066

EP - 1071

JO - Science

JF - Science

IS - 6007

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this