title: Sulfotyrosine recognition as marker for druggable sites in the extracellular space.
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.
authors: Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; E-Mails: jziarek@mcw.edu (J.J.Z.); mheroux@mcw.edu (M.S.H.); fpeterso@mcw.edu (F.C.P.).
authors: Joshua J
authors: JJ
authors: Ziarek
authors: Maxime S
authors: MS
authors: Heroux
authors: Christopher T
authors: CT
authors: Veldkamp
authors: Francis C
authors: FC
authors: Peterson
authors: Brian F
authors: BF
authors: Volkman
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D019743:Chemokines, CXC / Q000737:chemistry* / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D054387:Receptors, CXCR / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D019743:Chemokines, CXC; D008024:Ligands; D054387:Receptors, CXCR; C005662:tyrosine O-sulfate; D014443:Tyrosine