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Sci. Signal., 16 September 2008
Vol. 1, Issue 37, p. ra4
[DOI: 10.1126/scisignal.1160755]

RESEARCH

Structural Basis of CXCR4 Sulfotyrosine Recognition by the Chemokine SDF-1/CXCL12

Christopher T. Veldkamp1, Christoph Seibert2, Francis C. Peterson1, Norberto B. De la Cruz1, John C. Haugner III1, Harihar Basnet1, Thomas P. Sakmar2, and Brian F. Volkman1*

1 Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
2 Laboratory of Molecular Biology and Biochemistry, Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.

Abstract: Stem cell homing and breast cancer metastasis are orchestrated by the chemokine stromal cell–derived factor 1 (SDF-1) and its receptor CXCR4. Here, we report the nuclear magnetic resonance structure of a constitutively dimeric SDF-1 in complex with a CXCR4 fragment that contains three sulfotyrosine residues important for a high-affinity ligand-receptor interaction. CXCR4 bridged the SDF-1 dimer interface so that sulfotyrosines sTyr7 and sTyr12 of CXCR4 occupied positively charged clefts on opposing chemokine subunits. Dimeric SDF-1 induced intracellular Ca2+ mobilization but had no chemotactic activity; instead, it prevented native SDF-1–induced chemotaxis, suggesting that it acted as a potent partial agonist. Our work elucidates the structural basis for sulfotyrosine recognition in the chemokine-receptor interaction and suggests a strategy for CXCR4-targeted drug development.

* To whom correspondence should be addressed. E-mail: bvolkman{at}mcw.edu

Citation: C. T. Veldkamp, C. Seibert, F. C. Peterson, N. B. De la Cruz, J. C. Haugner, III, H. Basnet, T. P. Sakmar, B. F. Volkman, Structural Basis of CXCR4 Sulfotyrosine Recognition by the Chemokine SDF-1/CXCL12. Sci. Signal. 1, ra4 (2008).

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