Structure and dynamics of a functional cavity in the HIV-1 Envelope, and its role in conformational changes required for infection

HIV-1包膜功能腔的结构和动力学及其在感染所需构象变化中的作用

基本信息

  • 批准号:
    10083703
  • 负责人:
  • 金额:
    $ 20.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-01-09 至 2022-12-31
  • 项目状态:
    已结题

项目摘要

Structure and dynamics of a functional cavity in the HIV-1 Envelope, and its role in conformational changes required for infection Channels and cavities in protein structures often play an important role in modulating structure, function and dynamics. The HIV-1 Envelope (Env) glycoprotein, a conformational machine that utilizes receptor binding mediated conformational changes to effect virus and host cell membrane fusion, is riddled with cavities and channels. A highly conserved cavity – called the Phe43 cavity - engages the Phe43 residue of receptor CD4 and is critical for CD4-induced Env conformational transitions. The Phe43 cavity is also the binding site of broad and potent antibodies, drugs and peptide inhibitors of HIV-1 entry. The CD4-mimetic miniprotein M48U1, effects broad and potent HIV-1 neutralization, binds HIV-1 gp120 with pM affinity, showed efficacy as a vaginal microbicide in animal models, and more recently, was shown to synergize with the drug Tenofovir to inhibit HIV infection in activated PBMCs and human cervicovaginal histocultures. M48U1 inserts a methoxy cyclohexyl moiety to fill the Phe43 cavity. M48U1 and its analogs are the only class of ligands that reach deep into the Phe43 cavity, a property that makes them valuable tools for probing the structure of a deep, otherwise not easily accessible cavity.We have previously utilized M48U1 and its analogs to probe the structure of the Phe- 43 cavity in gp120 monomers. High resolution structures of M48U1 bound to HIV-1 Env gp120 revealed ligand flexibility, and the ability to fit within and adapt to the Phe43 cavities of diverse HIV-1 isolates with minimal perturbations of the cavity structure are key determinants of activity. In this grant we propose to explore the structure of the Phe43 cavity in the closed HIV-1 Env trimer using M48U1 as a molecular probe. The innovation in this grant derives from our use of M48U1 and its analogs as molecular probes of the Phe43 cavity, from the advances in cryo-EM technology that include improved specimen vitrification methods, improved microscope hardware, automated methods for high-throughput data collection, and advanced algorithms for data processing. These advances have recently allowed us to establish a rapid pipeline for determining high resolution structures of HIV-1 Env complexes. The scientific premise of this grant is that the Phe43 cavity is a critical functional component in HIV-1 Env, central to the activity of the CD4 receptor and many broad and potent antibodies and drugs. M48U1 is an exceptionally effective HIV-1 entry inhibitor, and one of the only ligands that fills the entire Phe-43 cavity. Exploring the structures of HIV-1 Env when bound to M48U1 will provide insights into the structure and the conformational constraints on the cavity in the closed state of the Env.
HIV-1囊膜功能腔的结构和动力学及其在构象变化中的作用 感染所需 蛋白质结构中的通道和空腔通常在调节结构、功能和功能方面发挥重要作用 动力学。HIV-1包膜糖蛋白,一种利用受体结合的构象机器 介导的构象变化影响病毒和宿主细胞膜的融合,布满空洞和 频道。一个高度保守的空洞--称为Phe43空洞--与CD4受体的Phe43残基结合 并且对CD4诱导的Env构象转变至关重要。Phe43空腔也是 广泛而有效的抗体、药物和多肽抑制剂进入HIV-1。模拟CD4的迷你蛋白M48U1, 广泛而有效的HIV-1中和作用,将HIV-1 gp120与PM亲和力结合,显示出作为阴道的有效性 动物模型中的杀微生物剂,以及最近被证明与药物替诺福韦协同作用,以抑制艾滋病毒 活化的PBMC和人宫颈阴道组织培养中的感染。M48U1插入甲氧基环己基 部分填充Phe43空洞。M48U1及其类似物是唯一一类深入到 Phe43腔,这一特性使它们成为探测深部结构的宝贵工具,否则就不是 我们以前已经利用M48U1及其类似物来探索Phe的结构- Gp120单体中有43个空腔。HIV-1环境蛋白gp120与M48U1结合的高分辨结构揭示 灵活性,以及在不同HIV-1分离株的Phe43洞内适配和适应的能力 腔结构的扰动是活性的关键决定因素。 在这项资助中,我们建议使用以下方法来探索封闭的HIV-1环境三聚体中Phe43空腔的结构 M48U1作为分子探针。这项授权的创新来自于我们使用M48U1及其类似物作为 Phe43腔的分子探针,来自低温电磁技术的进步,包括改进的 标本玻璃化方法、改进的显微镜硬件、高通量数据的自动化方法 集合,以及用于数据处理的高级算法。这些进步最近使我们能够 建立快速测定HIV-1包膜复合体高分辨结构的方法。科学的 这笔赠款的前提是Phe43空洞是HIV-1环境中的关键功能组件,对 CD4受体和许多广泛而有效的抗体和药物的活性。M48U1是一款特别的 有效的HIV-1进入抑制剂,也是填充整个Phe-43空腔的唯一配体之一。探索 当HIV-1 env与M48U1结合时,将提供对结构和构象的洞察 在环境的闭合状态下对型腔的约束。

项目成果

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Priyamvada Acharya其他文献

Priyamvada Acharya的其他文献

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{{ truncateString('Priyamvada Acharya', 18)}}的其他基金

Administrative Core
行政核心
  • 批准号:
    10643907
  • 财政年份:
    2022
  • 资助金额:
    $ 20.13万
  • 项目类别:
Effect of natural and engineered variations on structure and biophysics of SARS-CoV-2 spike
自然和工程变异对 SARS-CoV-2 刺突结构和生物物理学的影响
  • 批准号:
    10558637
  • 财政年份:
    2022
  • 资助金额:
    $ 20.13万
  • 项目类别:
Project 3 - Dynamics of latent HIV-1 reservoirs: High resolution antigenic mapping and strategies to block rebound
项目 3 - 潜在 HIV-1 储存库的动态:高分辨率抗原图谱和阻止反弹的策略
  • 批准号:
    10506669
  • 财政年份:
    2022
  • 资助金额:
    $ 20.13万
  • 项目类别:
Duke Center for HIV Structural Biology
杜克大学艾滋病毒结构生物学中心
  • 批准号:
    10643906
  • 财政年份:
    2022
  • 资助金额:
    $ 20.13万
  • 项目类别:
Core 1 - Structural Biology Core
核心 1 - 结构生物学核心
  • 批准号:
    10506664
  • 财政年份:
    2022
  • 资助金额:
    $ 20.13万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10506662
  • 财政年份:
    2022
  • 资助金额:
    $ 20.13万
  • 项目类别:
Dissecting the mechanisms of HIV resistance in vivo to broadly neutralizing antibodies
剖析 HIV 体内对广泛中和抗体的耐药机制
  • 批准号:
    10458981
  • 财政年份:
    2022
  • 资助金额:
    $ 20.13万
  • 项目类别:
Duke Center for HIV Structural Biology
杜克大学艾滋病毒结构生物学中心
  • 批准号:
    10506661
  • 财政年份:
    2022
  • 资助金额:
    $ 20.13万
  • 项目类别:
Core 1 - Structural Biology Core
核心 1 - 结构生物学核心
  • 批准号:
    10643911
  • 财政年份:
    2022
  • 资助金额:
    $ 20.13万
  • 项目类别:
Dissecting the mechanisms of HIV resistance in vivo to broadly neutralizing antibodies
剖析 HIV 体内对广泛中和抗体的耐药机制
  • 批准号:
    10680388
  • 财政年份:
    2022
  • 资助金额:
    $ 20.13万
  • 项目类别:

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