Structurally dissecting APOBEC3's for HIV-1 restriction and beyond
Structurally dissecting APOBEC3's for HIV-1 restriction and beyond
批准号:
10461788
负责人:
Celia A. Schiffer
金额:
$66.31万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
未结题
起止时间:
2016-09-01 至 2025-08-31
关键词:
Active SitesAddressBindingBiological AssayBiophysicsCatalytic DomainCell NucleusChemicalsChemistryCollaborationsComplementComplexCryo-electron tomographyCryoelectron MicroscopyCrystallizationCytidine DeaminaseDNADNA VirusesDataDeaminationDependovirusDinucleoside PhosphatesDouble Stranded DNA VirusDrug DesignEngineeringEnsureEnzymatic BiochemistryEnzymesEpitopesFamilyFutureGenomeGenomicsGoalsHIVHIV-1Head CancerHepatitis B VirusHerpesviridaeHumanHuman PapillomavirusImmune systemKnowledgeLaboratoriesLettersLibrariesMalignant NeoplasmsMalignant neoplasm of cervix uteriMalignant neoplasm of lungMalignant neoplasm of urinary bladderMutationNatural ImmunityNeck CancerNuclearNucleic AcidsOligonucleotidesPan GenusPositioning AttributeRNAReagentResearchRetrotransposonRetroviridaeRoentgen RaysRoleSeriesSingle Stranded DNA VirusSiteSourceSpecificityStructureSubstrate SpecificitySurfaceSystemTherapeuticTranslatingVariantViralViral GenomeVirionVirus Diseasesadaptive immunitychemotherapydesignexperienceinhibitorinterdisciplinary approachintermolecular interactionmalignant breast neoplasmmolecular modelingoverexpressionparticlepathogenstructural biologytherapeutic developmenttumorubiquitin-protein ligasevif Gene Productsvirology
中文摘要
结构解剖APOBEC 3用于HIV-1限制及其他
人体免疫系统保护我们免受病原体的侵害,但当
系统出错了。AID/APOBEC与先天免疫和适应性免疫有关,
酶的家族是胞苷脱氨酶,其在细胞内的不同作用仍然有限。
认识最初发现APOBEC 3(A3)的一个子集可以有效地限制
HIV-1,包括A3 G、A3 F和A3 H。这些限制性酶是如此强大,
进化出了“病毒体感染因子”蛋白Vif,通过劫持E3蛋白来对抗这种限制。
泛素连接酶和特异性靶向A3进行降解。随后的研究
揭示了A3的反应和限制病毒感染的能力是通过诱导
病毒基因组中的超突变,这不仅限于HIV,还扩展到其他
逆转录病毒和逆转录转座子。A3还限制DNA病毒,包括核病毒。
复制型ssDNA病毒如腺相关病毒和dsDNA病毒如
B型肝炎病毒、疱疹病毒和HPV。然而,A3活性可能是一把双刃剑,
剑如果没有适当的监管,DNA编辑APOBECs也可以访问
细胞核可以使自身基因组脱氨基,潜在地诱发癌症。当过度表达时,
A3 A、A3 B和A3 H已被描述为在哺乳动物中突变的主要内源性来源。
各种类型的人类癌症,如乳腺癌、膀胱癌、头颈癌、宫颈癌和肺癌
癌我们假设A3具有未实现的治疗潜力,无论是作为抗病毒,
通过阻断Vif结合重新激活天然抗HIV功能,
限制肿瘤内基因组多样性的化疗靶点。在本提案中,我们
通过多学科的方法,
结构生物学,生物物理学,酶学,化学和病毒学,以表征
A3对核酸和HIV-1 Vif的分子相互作用和差异特异性,
这些表位一旦被表征就将是未来治疗的靶位点。
发展
英文摘要
Structurally dissecting APOBEC3s for HIV-1 restriction and beyond
The human immune system protects us against pathogens but can cause problems when
the system goes awry. Implicated in both innate and adaptive immunity, the AID/APOBEC
family of enzymes are cytidine deaminases with differential roles of still limited
understanding. A subset of APOBEC3s (A3s) were initially discovered to potently restrict
HIV-1, including A3G, A3F and A3H. These restrictive enzymes are so potent that HIV
evolved the “virion infectivity factor” protein Vif to counter this restriction by hijacking an E3
ubiquitin ligase and specifically targeting A3s for degradation. Subsequent research has
revealed that A3’s ability to respond and restrict viral infection is by inducing
hypermutations in the viral genome, which is not limited to HIV but extends to other
retroviruses and retrotransposons. A3s also restrict DNA viruses, including nuclear
replicating ssDNA viruses such as adeno-associated virus and dsDNA viruses such as
hepatitis B virus, herpes viruses and HPV. However, A3 activity can be a double-edged
sword. If not properly regulated, DNA-editing APOBECs that also have access to the
nucleus can deaminate self-genomes, potentially instigating cancer. When overexpressed,
A3A, A3B and A3H have been described as a major endogenous source for mutations in
various types of human cancer, such as breast, bladder, head and neck, cervical, and lung
cancer. We hypothesize that A3s have unrealized therapeutic potentials, both as anti-viral
targets through reactivating the natural anti-HIV function by blocking Vif binding and as
targets for chemotherapy to restrict the genome diversity within tumors. In this proposal we
are leveraging our complementary strengths through a multi-disciplinary approach combining
structural biology, biophysics, enzymology, chemistry and virology, to characterize the
molecular interactions and differential specificities of A3s to nucleic acids and HIV-1 Vif, which
will provide epitopes that once characterized will be target sites for future therapeutic
development.
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会议论文
Integration of Evolution to Avoid Resistance in Structure Based Drug Design
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批准号:10388034
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项目类别:
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资助金额:$6.7万
-
财政年份:2020
-
负责人:Celia A. Schiffer
-
依托单位:
Integration of Evolution to Avoid Resistance in Structure Based Drug Design
-
批准号:10437865
-
项目类别:
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资助金额:$59.05万
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财政年份:2020
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负责人:Celia A. Schiffer
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依托单位:
Design of Protease Inhibitors to Target HTLV-1
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批准号:10201509
-
项目类别:
-
资助金额:$25.13万
-
财政年份:2020
-
负责人:Celia A. Schiffer
-
依托单位:
Integration of Evolution to Avoid Resistance in Structure Based Drug Design
-
批准号:10642936
-
项目类别:
-
资助金额:$58.04万
-
财政年份:2020
-
负责人:Celia A. Schiffer
-
依托单位:
Integration of Evolution to Avoid Resistance in Structure Based Drug Design
-
批准号:10256048
-
项目类别:
-
资助金额:$59.92万
-
财政年份:2020
-
负责人:Celia A. Schiffer
-
依托单位:
Design of Protease Inhibitors to Target HTLV-1
-
批准号:10057413
-
项目类别:
-
资助金额:$20.94万
-
财政年份:2020
-
负责人:Celia A. Schiffer
-
依托单位:
Structurally dissecting APOBEC3's for HIV-1 restriction
-
批准号:9340247
-
项目类别:
-
资助金额:$59.25万
-
财政年份:2016
-
负责人:Celia A. Schiffer
-
依托单位:
Structurally dissecting APOBEC3's for HIV-1 restriction and beyond
-
批准号:10082374
-
项目类别:
-
资助金额:$70.23万
-
财政年份:2016
-
负责人:Celia A. Schiffer
-
依托单位:
Structurally dissecting APOBEC3's for HIV-1 restriction and beyond
-
批准号:10682566
-
项目类别:
-
资助金额:$65.08万
-
财政年份:2016
-
负责人:Celia A. Schiffer
-
依托单位:
Structurally dissecting APOBEC3's for HIV-1 restriction
-
批准号:9769778
-
项目类别:
-
资助金额:$58.24万
-
财政年份:2016
-
负责人:Celia A. Schiffer
-
依托单位:
Structurally dissecting APOBEC3's for HIV-1 restriction
-
批准号:9080050
-
项目类别:
-
资助金额:$61.42万
-
财政年份:2016
-
负责人:Celia A. Schiffer
-
依托单位:
The Interdependency of Drug Resistance Evolution and Drug Design: HIV-1 Protease
-
批准号:8912508
-
项目类别:
-
资助金额:$156.05万
-
财政年份:2014
-
负责人:Celia A. Schiffer
-
依托单位:
The Interdependency of Drug Resistance Evolution and Drug Design: HIV-1 Protease
-
批准号:8789525
-
项目类别:
-
资助金额:$171.08万
-
财政年份:2014
-
负责人:Celia A. Schiffer
-
依托单位:
The Interdependency of Drug Resistance Evolution and Drug Design: HIV-1 Protease
-
批准号:9321824
-
项目类别:
-
资助金额:$156.05万
-
财政年份:2014
-
负责人:Celia A. Schiffer
-
依托单位:
Macromolecular Crystallographic HighFlux Home Lab X-ray Diffraction System
-
批准号:8247330
-
项目类别:
-
资助金额:$53.1万
-
财政年份:2012
-
负责人:Celia A. Schiffer
-
依托单位:
Structural Characterization of APOBECS's Atomic interactions
-
批准号:8078336
-
项目类别:
-
资助金额:$35.01万
-
财政年份:2011
-
负责人:Celia A. Schiffer
-
依托单位:
STRUCTURAL STUDIES OF VIRAL PROTEASES: HIV-1 PROTEASE AND HCV NS3 PROTEASE
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批准号:8363697
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项目类别:
-
资助金额:$2.16万
-
财政年份:2011
-
负责人:Celia A. Schiffer
-
依托单位:
UNDERSTANDING DRUG RESISTANCE MECHANISMS OF HIV-1 PROTEASE
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批准号:8170620
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项目类别:
-
资助金额:$0.7万
-
财政年份:2010
-
负责人:Celia A. Schiffer
-
依托单位:
Drug Resistance in HCV NS3/4A - Inhibitor binding versus substrate recognition
-
批准号:8452658
-
项目类别:
-
资助金额:$38.27万
-
财政年份:2010
-
负责人:Celia A. Schiffer
-
依托单位:
Elucidating the Intermolecular Interfaces of APOBEC3's
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批准号:7930226
-
项目类别:
-
资助金额:$22.77万
-
财政年份:2010
-
负责人:Celia A. Schiffer
-
依托单位:
海外基金