Sulfotyrosine Recognition as Marker for Druggable Sites in the Extracellular Space

International Journal of Molecular Sciences

Joshua J. Ziarek²  Maxime S. Heroux²  Christopher T. Veldkamp¹  Francis C. Peterson² 

[1] Department of Chemistry, University of Wisconsin-Whitewater, 800 West Main Street, Whitewater, WI 53190, USA; E-Mail:;Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; E-Mails:

关键词: chemokine;    sulfotyrosine;    NMR;    structure;    alignment;    drug discovery;   

DOI  :  10.3390/ijms12063740

来源: mdpi

【 摘 要 】

Chemokine signaling is a well-known agent of autoimmune disease, HIV infection, and cancer. Drug discovery efforts for these signaling molecules have focused on developing inhibitors targeting their associated G protein-coupled receptors. Recently, we used a structure-based approach directed at the sulfotyrosine-binding pocket of the chemokine CXCL12, and thereby demonstrated that small molecule inhibitors acting upon the chemokine ligand form an alternative therapeutic avenue. Although the 50 members of the chemokine family share varying degrees of sequence homology (some as little as 20%), all members retain the canonical chemokine fold. Here we show that an equivalent sulfotyrosine-binding pocket appears to be conserved across the chemokine superfamily. We monitored sulfotyrosine binding to four representative chemokines by NMR. The results suggest that most chemokines harbor a sulfotyrosine recognition site analogous to the cleft on CXCL12 that binds sulfotyrosine 21 of the receptor CXCR4. Rational drug discovery efforts targeting these sites may be useful in the development of specific as well as broad-spectrum chemokine inhibitors.

【 授权许可】

CC BY   
© 2011 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.