Regulating Migration

The migration of cells around the body is an important factor in cancer development and the establishment of infection. Movement is induced by small proteins called chemokines, and so for a specific function, migration is controlled by a relevant chemokine binding to its respective receptor. This family of receptors is known as guanine (G) protein–coupled receptors, which span cell membranes to mediate between external signals from chemokines and internal mechanisms. The chemokine receptor CXCR4 is implicated in many types of cancer and in infection, and Wu et al. (p. 1066, published online 7 October; see the Report by Chien et al.) report on a series of crystal structures obtained for CXCR4 bound to small molecules. In every case, the same homodimer structure was observed, suggesting that the interface is functionally relevant. These structures offer insights into the interactions between CXCR4 and its natural chemokine, as well as with the virus HIV-1.


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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Volume 330 | Issue 6007
19 November 2010

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Received: 29 June 2010
Accepted: 2 September 2010
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This work was supported in part by the Protein Structure Initiative grant U54 GM074961 for structure production, NIH Roadmap Initiative grant P50 GM073197 for technology development, NIH grants R21 RR025336 and R21 AI087189 to V.C., and Pfizer. T.M.H. acknowledges support from NIH R01 AI037113 and R01 GM081763, D.J.H. from F32 GM083463, and R.A. from R01 GM071872. The authors thank J. Velasquez for help on molecular biology, T. Trinh and K. Allin for help on baculovirus expression, I. Wilson and D. Burton for careful review and scientific feedback on the manuscript, W. Schief for electron microscopy models of gp120-gp41-CD4 complex, G. W. Han for evaluating the structure quality and preparation for PDB submission, and A. Walker for assistance with manuscript preparation. The authors acknowledge E. La Chapelle on chemistry tool compound synthesis; A. Rane on radiolabeling of [3H]BIMA; M. Cui for help developing [3H]BIMA binding assay; Y. Zheng, The Ohio State University, and M. Caffrey, Trinity College (Dublin, Ireland), for the generous loan of the in meso robot [built with support from the National Institutes of Health (GM075915), the NSF (IIS0308078), and Science Foundation Ireland (02-IN1-B266)]; and J. Smith, R. Fischetti, and N. Sanishvili at the General Medicine and Cancer Institutes Collaborative Access Team (GM/CA-CAT) beamline at the Advanced Photon Source for assistance in development and use of the minibeam and beamtime. The GM/CA-CAT beamline (23-ID) is supported by the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Sciences (Y1-GM-1104). R.C.S. is the founder and is a board member of Receptos, a biotech company focused on GPCR structure–based drug discovery. Transfer of IT1t, CVX15, and [3H]BIMA will require a Material Transfer Agreement (MTA) with Pfizer, and transfer of all other constructs and biological materials requires an MTA with the Scripps Research Institute. Atomic coordinates and structure factors have been deposited in the Protein Data Bank with identification codes 3ODU (CXCR4-2–IT1t, P21), 3OE0 (CXCR4-3–CVX15, C2), 3OE8 (CXCR4-2–IT1t, P1), 3OE9 (CXCR4-3–IT1t, P1), and 3OE6 (CXCR4-1–IT1t, I222).



Beili Wu
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Ellen Y. T. Chien
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Clifford D. Mol
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Gustavo Fenalti
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Wei Liu
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Vsevolod Katritch
Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Ruben Abagyan
Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Alexei Brooun
Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA.
Peter Wells
Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA.
F. Christopher Bi
Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA.
Damon J. Hamel
Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Peter Kuhn
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Tracy M. Handel
Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Vadim Cherezov
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Raymond C. Stevens* [email protected]
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.


To whom correspondence should be addressed. E-mail: [email protected]

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