Research ArticleStructural Biology

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

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Sci. Signal.  16 Sep 2008:
Vol. 1, Issue 37, pp. ra4
DOI: 10.1126/scisignal.1160755

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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.

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