Sulfotyrosine recognition as marker for druggable sites in the extracellular space.

Joshua J Ziarek,Maxime S Heroux,Christopher T Veldkamp,Francis C Peterson,Brian F Volkman

doi:10.3390/ijms12063740

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.

Highlights

The normal function of chemokines is to direct the migration of cells during development, inflammation, and hematopoietic stem cell mobilization
Primary protein sequence alignment is a classic method of probing evolutionary conservation and homology
The N-terminus preceding the first conserved cysteine is highly disordered and the C-terminal helix orientation is dependent on solution condition and oligomeric state [33,34]; only the amino acids comprising the beta sheet of each chemokine were considered

Summary

Introduction

The normal function of chemokines is to direct the migration of cells during development, inflammation, and hematopoietic stem cell mobilization. As chemokines are secreted into the extracellular space, they bind to glycosaminoglycans present on the exterior of most cells, and establish a concentration gradient. Cells that express the G protein-coupled receptor (GPCR) specific for that chemokine migrate toward the origin of secretion. When the ability to traffic cells is hijacked, the chemokine network can maintain and coordinate many disease states. Chemokine signaling has been implicated in various autoimmune diseases, such as: multiple sclerosis, rheumatoid arthritis, and atherosclerosis (as reviewed by [1,2,3]). Though canonically associated with directing cancer metastases [4], the role of chemokines in tumor progression has been expanded to both growth and neovascularization (reviewed by [5])

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