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

Overview

Journal Sci Signal

Specialties Cell Biology
Physiology
Science

Date 2008 Sep 19

PMID 18799424

Citations 167

Authors

Christopher T Veldkamp

Christoph Seibert

Francis C Peterson

Norberto B de la Cruz

John C Haugner 3rd

Harihar Basnet

Thomas P Sakmar

Brian F Volkman

Affiliations

Soon will be listed here.

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.

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