An inter-switch between hydrophobic and charged amino acids generated druggable small molecule binding pocket in chemokine paralog CXCL3.

Multigene families such as chemokines arose as a result of gene duplication events, followed by mutations and selection. GRO chemokines are three duplicated CXCL genes, comprising of CXCL1, CXCL2 and CXCL3 proteins. Comparative structural analysis of the two closely related paralog chemokines CXCL2 and CXCL3 in the current study indicated a variable electrostatic surface between them, and a specific hydrophobic pocket on the surface of CXCL3 that can bind naphthalene derivatives. Combined fluorescence and NMR analyses revealed that CXCL3 monomer can specifically bind to ANS (8-Anilinonaphthalene-1-sulfonic acid) with a stoichiometry of 1:1 by involving the residues belonging to the structural elements 3₁₀ helix and the α-helix. A close observation of the surfaces of these paralogs suggested that such a hydrophobic pocket is a resultant of inter-switch between a charged and a hydrophobic residue on the primary sequence of the two paralog proteins. Interestingly, the hydrophobic pocket is in the vicinity of GAG binding region of CXCL3, a molecular determinant in leukocyte trafficking. Such unique pockets/patches on specific chemokine surfaces can be exploited to design the naphthalene/small molecule based inhibitors against GAG binding to regulate their molecular interactions during the onset and progression of various types of cancers and inflammatory diseases.

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