A ubiquitous feature of inflammation is the accumulation of leukocytes in the inflamed tissue. One consequence of leukocyte accumulation is the degradation of otherwise healthy tissue. Thus, a promising strategy against many inflammatory diseases is to inhibit leukocyte migration. Leukocyte migration is initiated by the binding of chemokines (small, soluble proteins) to their receptors (G-protein-coupled receptors located on the leukocyte surface). The expression patterns of chemokines and chemokine receptors and the specificity of chemokine-receptor interactions are central to the control of selective leukocyte trafficking during inflammation. The proposed research addresses each of the following questions: (1) What are the factors that determine specific binding between chemokines and their receptors? (i.e. the binding of individual chemokines to one receptor but not another); and (2) What is the structural basis of chemokine-receptor binding and specificity? The work will focus on the specific interaction between the chemokine eotaxin and its receptor CCR3, which results in the recruitment of eosinophils, a feature of allergic and parasitic diseases. Mutational studies of eotaxin and CCR3 will be performed to identify structural features that are critical to high affinity, specific binding. The possibility that CCR3 (and/or glycosaminoglycans) induce(s) eotaxin dimerization on the cell surface will be tested using fluorescence resonance energy transfer. In addition, soluble peptides and proteins that mimic segments of CCR3 will be used to derive structural and dynamical information about the eotaxin-CCR3 interaction. Finally, the information from these various approaches will be combined in an effort to model the structure of the eotaxin-CCR3 complex. The principles learned from this study are likely to be applicable to other chemokines-receptor interactions and may help guide efforts to develop more specific anti-inflammatory therapies.
| Barter, Emily F; Stone, Martin J (2012) Synergistic interactions between chemokine receptor elements in recognition of interleukin-8 by soluble receptor mimics. Biochemistry 51:1322-31 |
| Simpson, Levi S; Zhu, John Z; Widlanski, Theodore S et al. (2009) Regulation of chemokine recognition by site-specific tyrosine sulfation of receptor peptides. Chem Biol 16:153-61 |
