Modelling of the membrane receptor CXCR3 and its complexes with CXCL9, CXCL10 and CXCL11 chemokines: putative target for new drug design.
The chemokines play a key role in immune and inflammatory responses by promoting recruitment and activation of different subpopulations of leukocytes. These comprise over 50 proteins grouped into four classes, in basis to the arrangement of conserved cysteine residues within the sequence. CXCL9, CXCL10 and CXCL11 are the members of the family of ELR-CXC chemokines and bind the same CXCR3 receptor. During the past few years, several studies have demonstrated a pathogenetic role of CXCR3 and its ligands in many human inflammatory diseases. The blockade of CXCR3 interactions with its ligands has been suggested as a possible therapeutic target for the treatment of these diseases. Therefore, we modelled the three-dimensional structure of CXCL9 and CXCR3, and, successively, of the CXCL9/CXCR3 complex in comparison to CXCL10/CXCR3 and CXCL11/CXCR3 complexes. We have then shown the structural determinants of these interactions and their physico-chemical features. Finally, the interaction residues involved in the formation of the complexes have been highlighted and analyzed in order to be used for drug design.
Department of Biochemistry and Biophysics and Interdepartmental Research Center for Computational and Biotechnological Sciences, Second University of Naples, via Costantinopoli 16, 80138 Naples, Italy.
Tiziana
T
Trotta
Susan
S
Costantini
Giovanni
G
Colonna
D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002462:Cell Membrane / Q000737:chemistry*; D054357:Chemokine CXCL10 / Q000737:chemistry*; D054371:Chemokine CXCL11 / Q000737:chemistry*; D054370:Chemokine CXCL9 / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D054367:Receptors, CXCR3 / Q000737:chemistry*; D012243:Rhodopsin / Q000737:chemistry; D016415:Sequence Alignment; D013499:Surface Properties; D013816:Thermodynamics
D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D054367:Receptors, CXCR3; D012243:Rhodopsin