Chemokine receptor CXCR3: Allosteric binding site mapping by photoaffinity labeling and site-directed mutagenesis

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The CXCR3 receptor is implicated in various pathological conditions, including autoimmune diseases (e.g., multiple sclerosis, psoriasis, and rheumatoid arthritis), transplant rejection, cancer, development and dissemination of metastases. The compounds having CXCR3 inhibitory activity would be very useful in treating or preventing these diseases. Despite the fact that CXCR3 counts as a very attractive pharmacological target, the receptor-ligand interactions responsible for the high affinity and noncompetitive (allosteric) antagonism are not yet structurally and functionally characterized. The main aspect of this research proposal is the structural and functional characterization of CXCR3 allosteric binding pocket used by AMG487. The photoaffinity labeling followed by mass spectrometry will be applied. Photoactivatable ligands are tools used in drug discovery and development, facilitating the identification of the binding site on the target protein. Additionally, site-directed mutagenesis and homology modeling will be used to complement the photoaffinity labeling experiments. With the aid of novel ligands, which are currently synthesized in my research group, the validation of obtained homology model and identified binding pocket will be preformed. The expected outcomes are the structural and functional description of allosteric binding pocket of CXCR3 and the accompanying pharmacophore model.