Year: 2011
Type: article
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.
DOI: 10.3390/ijms12063740
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
Awards: Structural Basis for Chemokine Function, G1965559398, G230966950, G2669440613, Sulfotyrosine-guided discovery of small molecule chemokine inhibitors, Conformational duality in the human chemokine Ltn/XCL1, Conformational duality in the human chemokine Ltn/XCL1, Structural studies of chemokines that target metastatic cancer cells to the lymph, G9000215711, G9000331475, Structural Basis for Chemokine Function
OpenAlex ID: W2004471062