4.7 Article

Sulfotyrosine Recognition as Marker for Druggable Sites in the Extracellular Space

Journal

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 12, Issue 6, Pages 3740-3756

Publisher

MDPI AG
DOI: 10.3390/ijms12063740

Keywords

chemokine; sulfotyrosine; NMR; structure; alignment; drug discovery

Funding

  1. NIH [AI058072, AI063325, 1R15CA159202-01]
  2. State of Wisconsin Cancer Research Grant
  3. New England Division
  4. UWW

Ask authors/readers for more resources

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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available