The structural basis of homo- and heterodimerization of two chemokine receptors: Implications in HIV-1 cell entry

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SUMMARY The chemokine receptors CCR5 and CXCR4 play essential roles in the human immune system and are involved in HIV infection and cancer metastasis. Several studies have demonstrated the role of homo- and heterodimerization of these receptors in modulating protein function by affecting their chemokine sensitivity or altering their G protein coupling mechanisms. Moreover, the ability of HIV to infect T cells utilizing either CXCR4 or CCR5 as a co-receptor has been shown to depend on homo- and heterodimerization. Consequently, the association of these two chemokine receptors has increasingly gained attention for drug design. At this time, there is no high-resolution structure available for CCR5 or CXCR4 homo- or heterodimers due to the complexity of the crystallization and sample preparation for EM. In aim 1, we will study the dimerization of CCR5 protein at both molecular and functional levels. In aim 2, we will study the heterodimerization of CCR5 and CXCR4. In aim 3, we will develop a nanodisc-based fusion assay. Moreover, we will image HIV pseudovirus particles binding and fusion with large nanodiscs containing CD4/CCR5 or CD4/CXCR4.