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
- 来源:
- 关键词:AdoptedAffectAffinityAlgorithmsAnimal ModelAntibodiesAtopobium vaginaeBindingBinding SitesBiological AssayCD4 AntigensCase StudyCell membraneCell surfaceCollaborationsComplementComplexCryoelectron MicroscopyCrystallizationDataData CollectionDrug DesignEvolutionGlycoproteinsGoalsGrantHIV Envelope Protein gp120HIV InfectionsHIV-1HandHumanInfectionInvestigationLabelLettersLigandsMeasuresMechanicsMediatingMembrane FusionMethodsMicroscopeMolecularMolecular ConformationMolecular ProbesMovementPeptidesPeripheral Blood Mononuclear CellPharmaceutical PreparationsPlayPropertyPublishingResolutionRoleSpecimenStructureTechnologyTenofovirVaccine DesignVariantVirusWritinganalogcervicovaginalcomputerized data processingconformational conversionexpectationexperimental studyflexibilityimprovedinhibitor/antagonistinnovationinsightmimeticsmonomerprotein structurereceptor bindingsimulationtooltrendvaginal microbicide
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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
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:
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:
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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