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Int. J. Mol. Sci. 2017, 18(3), 508; doi:10.3390/ijms18030508

Structural Basis of Native CXCL7 Monomer Binding to CXCR2 Receptor N-Domain and Glycosaminoglycan Heparin

Department of Biochemistry and Molecular Biology, and Sealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch, Galveston, TX 77555, USA
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Academic Editor: Martin J. Stone
Received: 13 January 2017 / Revised: 14 February 2017 / Accepted: 21 February 2017 / Published: 26 February 2017
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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Abstract

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. View Full-Text
Keywords: chemokine; CXCL7; NAP-2; CXCR2; glycosaminoglycan; heparin; NMR; monomer chemokine; CXCL7; NAP-2; CXCR2; glycosaminoglycan; heparin; NMR; monomer
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Brown, A.J.; Sepuru, K.M.; Rajarathnam, K. Structural Basis of Native CXCL7 Monomer Binding to CXCR2 Receptor N-Domain and Glycosaminoglycan Heparin. Int. J. Mol. Sci. 2017, 18, 508.

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