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Sulfotyrosine recognition as marker for druggable sites in the extracellular space. Int J Mol Sci 2011;12(6):3740-56

Date

07/13/2011

Pubmed ID

21747703

Pubmed Central ID

PMC3131587

DOI

10.3390/ijms12063740

Scopus ID

2-s2.0-79959708032   11 Citations

Abstract

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 BF

Authors

Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of Wisconsin
Brian 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 Sequence
Binding Sites
Chemokines, CXC
Extracellular Space
Humans
Ligands
Magnetic Resonance Spectroscopy
Molecular Dynamics Simulation
Molecular Sequence Data
Protein Structure, Tertiary
Receptors, CXCR
Sequence Alignment
Tyrosine
jenkins-FCD Prod-461 7d7c6113fc1a2757d2947d29fae5861c878125ab