This project is concerned with the characterization of structures and interactions of chemokine receptors and their role in human immunodeficiency virus type 1 (HIV-1) infection. Recently, several chemokine receptors such as CCR5 were discovered to be the coreceptors for HIV-1 to bind and enter the cells. Together with the main receptor CD4, these chemokine coreceptors ply an important role in HIV-1 pathogenesis. The natural ligands of these chemokine receptors, such as CCR5 ligand macrophage inflammatory protein 1-beta (MIP-1-beta), were shown to inhibit HIV-1 infection. The applicants propose to use the complex between CCR5 and MIP-1-beta as a model system to develop a general understanding of the interactions of chemokine receptors with their natural ligands and HIV-1. To this end, structural and chemical approaches are used to formulate a series of protein modeling and peptide synthesis experiments. In preliminary studies, the applicant has carried out computer modeling studies to produce a three-dimensional structure of the CCR5-MIP-1-beta complex. Analysis of this structure has not only provided a plausible basis to explain current data from genetic and molecular biological experiments but also revealed new functional sites in MIP-1-beta and CCR5. These observations have led the applicant to design a series of peptide analogs to test hypothesis about the structure-function of MIP-1-beta. Two synthetic peptides derived from the predicted binding sites of MIP-1-beta displayed biological activity in blocking MIP-1-beta binding to CCR5. In this proposal, the applicant plan to extend these studies to further characterize the structure-function relationship of these identified regions and other potential functional sites in MIP-1-beta and CCR5. This research will focus on the close interplay between theoretical computational modeling and peptide chemical synthesis and binding experiments.
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