Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12. Sci Signal 2008 Sep 16;1(37):ra4
Date
09/19/2008Pubmed ID
18799424Pubmed Central ID
PMC2692298DOI
10.1126/scisignal.1160755Scopus ID
2-s2.0-54849434087 (requires institutional sign-in at Scopus site) 267 CitationsAbstract
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.
Author List
Veldkamp CT, Seibert C, Peterson FC, De la Cruz NB, Haugner JC 3rd, Basnet H, Sakmar TP, Volkman BFAuthors
Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of WisconsinBrian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Amino Acid SequenceCalcium
Cell Line
Chemokine CXCL12
Chemotaxis, Leukocyte
Dimerization
Humans
Models, Molecular
Molecular Sequence Data
Nuclear Magnetic Resonance, Biomolecular
Protein Conformation
Receptors, CXCR4
Tyrosine
