Investigating the mechanism of action of small-molecule modulators at the human CXCR2 receptor

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The CXCR2 chemokine receptor has emerged as a target of such a class of inhibitors but it is currently unknown whether these drugs truly affect the binding of the orthosteric ligand via an allosteric mechanism or they compete for binding with arrestins and G proteins. As the interface between the receptor and effectors such as G proteins, beta arrestins and GRKs is different, it would also be of importance to investigate whether the CXCR2 small-molecule antagonists differentially affect the coupling of the different effectors acting as 'biased' ligands. The kinetics of binding of the modulators and its effect on CXCR2 signalling is another area open for investigation. Using the CXCR2 receptor with a range of structurally distinct small-molecule allosteric modulators available, these concepts will be explored in whole cell pharmacological assays (including novel split luciferase based assays for protein-protein interactions). In due course, the project would further develop an assay to directly probe the modulators and G protein competition in an isolated purified CXCR2 system.