Sulfotyrosine recognition as marker for druggable sites in the extracellular space. Int J Mol Sci 2011;12(6):3740-56
Date
07/13/2011Pubmed ID
21747703Pubmed Central ID
PMC3131587DOI
10.3390/ijms12063740Scopus ID
2-s2.0-79959708032 (requires institutional sign-in at Scopus site) 14 CitationsAbstract
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.
Author List
Ziarek JJ, Heroux MS, Veldkamp CT, Peterson FC, 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 SequenceBinding Sites
Chemokines, CXC
Extracellular Space
Humans
Ligands
Magnetic Resonance Spectroscopy
Molecular Dynamics Simulation
Molecular Sequence Data
Protein Structure, Tertiary
Receptors, CXCR
Sequence Alignment
Tyrosine
