CXCL7, a chemokine highly expressed in platelets, orchestrates neutrophil 
recruitment during thrombosis and related pathophysiological processes by 
interacting with CXCR2 receptor and sulfated glycosaminoglycans (GAG). CXCL7 
exists as monomers and dimers, and dimerization (~50 μM) and CXCR2 binding (~10 
nM) constants indicate that CXCL7 is a potent agonist as a monomer. Currently, 
nothing is known regarding the structural basis by which receptor and GAG 
interactions mediate CXCL7 function. Using solution nuclear magnetic resonance 
(NMR) spectroscopy, we characterized the binding of CXCL7 monomer to the CXCR2 
N-terminal domain (CXCR2Nd) that constitutes a critical docking site and to GAG 
heparin. We found that CXCR2Nd binds a hydrophobic groove and that ionic 
interactions also play a role in mediating binding. Heparin binds a set of 
contiguous basic residues indicating a prominent role for ionic interactions. 
Modeling studies reveal that the binding interface is dynamic and that GAG 
adopts different binding geometries. Most importantly, several residues involved 
in GAG binding are also involved in receptor interactions, suggesting that 
GAG-bound monomer cannot activate the receptor. Further, this is the first study 
that describes the structural basis of receptor and GAG interactions of a native 
monomer of the neutrophil-activating chemokine family.