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

两种趋化因子受体同二聚和异二聚的结构基础：对 HIV-1 细胞进入的影响

• 批准号: 10455267
• 负责人: Mahmoud Nasr
• 金额: $ 75.81万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455267
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Agonist; Attention; Binding; Biological Assay; CCR5 gene; CXCR4 gene; Cells; Communicable Diseases; Complement; Complex; Coupling; Cryoelectron Microscopy; Crystallization; Development; Dimerization; Dissociation; Drug Design; Drug Targeting; Electrophysiology (science); Fluorescence Microscopy; GTP-Binding Proteins; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Heterodimerization; Homo; Human; Image; Immune system; Ligands; Lipids; Membrane Lipids; Molecular; Negative Staining; Neoplasm Metastasis; Neurotensin Receptors; Physiological; Play; Predisposition; Preparation; Proteins; Recording of previous events; Reporting; Resolution; Role; Sampling; Structure; T-Lymphocyte; Techniques; Time; Virus; base; cell type; chemokine; chemokine receptor; dimer; drug development; experimental study; insight; luminescence; nanodisk; new therapeutic target; novel; particle; patch clamp; protein function; receptor; reconstitution; response; single molecule; tool

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.

概括 趋化因子受体CCR5和CXCR4在人免疫系统中起着重要作用，并且是 参与HIV感染和癌症转移。几项研究表明了同性恋的作用 这些受体在调节蛋白质功能方面的异二二聚体，通过影响其趋化因子敏感性或 改变其G蛋白偶联机制。此外，HIV感染T细胞的能力利用了任何一种 CXCR4或CCR5作为共受体，已证明取决于同二聚体和异二聚化。 因此，这两个趋化因子受体的关联已越来越引起人们对药物的关注 设计。目前，CCR5或CXCR4均或异二聚体尚无高分辨率结构 由于结晶和EM样品制备的复杂性。在AIM 1中，我们将研究 CCR5蛋白在分子水平和功能水平上的二聚化。在AIM 2中，我们将研究 CCR5和CXCR4的异二聚化。在AIM 3中，我们将开发基于纳米轴的融合测定法。而且， 我们将与包含CD4/CCR5或 CD4/CXCR4。

项目成果

Circularized Nanodiscs for Multivalent Mosaic Display of SARS-CoV-2 Spike Protein Antigens.

• DOI: 10.3390/vaccines11111655
• 发表时间: 2023-10-28
• 期刊: Vaccines
• 影响因子: 7.8
• 作者: Mabrouk MT;Zidan AA;Aly N;Mohammed MT;Ghantous F;Seaman MS;Lovell JF;Nasr ML
• 通讯作者: Nasr ML