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Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12.

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.

SUBMITTER: Veldkamp CT

PROVIDER: S-EPMC2692298 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12.

Veldkamp Christopher T CT Seibert Christoph C Peterson Francis C FC De la Cruz Norberto B NB Haugner John C JC Basnet Harihar H Sakmar Thomas P TP Volkman Brian F BF

Science signaling 20080916 37

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 oppos ...[more]

PMID: 18799424

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