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

总结 趋化因子受体CCR 5和CXCR 4在人类免疫系统中起重要作用， 参与HIV感染和癌症转移。一些研究已经证明了同性恋和 这些受体在通过影响其趋化因子敏感性调节蛋白质功能中的异二聚化，或 改变它们的G蛋白偶联机制。此外，HIV感染T细胞的能力， CXCR 4或CCR 5作为共受体已显示依赖于同源和异源二聚化。 因此，这两种趋化因子受体的联合越来越受到药物治疗的关注。 设计此时，没有可用于CCR 5或CXCR 4同源或异源二聚体的高分辨率结构 由于EM的结晶和样品制备的复杂性。在目标1中，我们将研究 CCR 5蛋白在分子和功能水平上的二聚化。在目标2中，我们将研究 CCR 5和CXCR 4的异二聚化。在目标3中，我们将开发基于纳米盘的融合测定。此外，委员会认为， 我们将对HIV假病毒颗粒与含有CD 4/CCR 5或 CD4/CXCR4。

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.