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.

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。

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