Structurally dissecting APOBEC3's for HIV-1 restriction and beyond
从结构上剖析 APOBEC3 的 HIV-1 限制及其他限制
基本信息
- 批准号:10082374
- 负责人:
- 金额:$ 70.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:Active SitesAddressAntiviral AgentsBindingBiological 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 SpecificitySurfaceSystemTherapeuticTranslatingVariantViral GenomeVirionVirus Diseasesadaptive immunitychemotherapydesignexperienceinhibitor/antagonistinterdisciplinary approachintermolecular interactionmalignant breast neoplasmmolecular modelingoverexpressionparticlepathogenstructural biologystructured datatherapeutic developmenttumorubiquitin-protein ligasevif Gene Productsvirology
项目摘要
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.
从结构上剖析APOBEC3s对HIV-1的限制
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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Celia A. Schiffer其他文献
Non-canonical pattern recognition of a pathogen-derived metabolite by a nuclear hormone receptor identifies virulent bacteria in emC. elegans/em
核激素受体对病原体衍生代谢物的非典型模式识别在秀丽隐杆线虫中鉴定出有毒细菌
- DOI:
10.1016/j.immuni.2023.01.027 - 发表时间:
2023-04-11 - 期刊:
- 影响因子:26.300
- 作者:
Nicholas D. Peterson;Samantha Y. Tse;Qiuyu Judy Huang;Khursheed A. Wani;Celia A. Schiffer;Read Pukkila-Worley - 通讯作者:
Read Pukkila-Worley
Activation Of Interferon Regulatory Factors Revealed By The Crystal Structure Of Dimeric IRF-5
- DOI:
10.1016/j.bpj.2008.12.3070 - 发表时间:
2009-02-01 - 期刊:
- 影响因子:
- 作者:
William E. Royer;Weijun Chen;Suvana S. Lam;Hema Srinath;Zhaozhao Jiang;John J. Correia;Celia A. Schiffer;Katherine A. Fitzgerald;Kai Lin - 通讯作者:
Kai Lin
Using Molecular Dynamics to Investigate Substrate Recognition and Co-evolution in HIV-1 Protease
- DOI:
10.1016/j.bpj.2008.12.3129 - 发表时间:
2009-02-01 - 期刊:
- 影响因子:
- 作者:
Aysegul Ozen;Turkan Haliloglu;Celia A. Schiffer - 通讯作者:
Celia A. Schiffer
Accounting for molecular mobility in structure determination based on nuclear magnetic resonance spectroscopic and X-ray diffraction data.
基于核磁共振波谱和 X 射线衍射数据的结构测定中的分子迁移率。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:0
- 作者:
W. V. Gunsteren;R. Brunne;P. Gros;René C. van Schaik;Celia A. Schiffer;A. Torda - 通讯作者:
A. Torda
Structural Insights into Calmodulation of Neuronal KCNQ Channels
- DOI:
10.1016/j.bpj.2011.11.098 - 发表时间:
2012-01-31 - 期刊:
- 影响因子:
- 作者:
Karen Mruk;Shivender M.D. Shandilya;Robert O. Blaustein;Celia A. Schiffer;William R. Kobertz - 通讯作者:
William R. Kobertz
Celia A. Schiffer的其他文献
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{{ truncateString('Celia A. Schiffer', 18)}}的其他基金
Integration of Evolution to Avoid Resistance in Structure Based Drug Design
整合进化以避免基于结构的药物设计中的耐药性
- 批准号:
10388034 - 财政年份:2020
- 资助金额:
$ 70.23万 - 项目类别:
Integration of Evolution to Avoid Resistance in Structure Based Drug Design
整合进化以避免基于结构的药物设计中的耐药性
- 批准号:
10437865 - 财政年份:2020
- 资助金额:
$ 70.23万 - 项目类别:
Design of Protease Inhibitors to Target HTLV-1
针对 HTLV-1 的蛋白酶抑制剂的设计
- 批准号:
10201509 - 财政年份:2020
- 资助金额:
$ 70.23万 - 项目类别:
Integration of Evolution to Avoid Resistance in Structure Based Drug Design
整合进化以避免基于结构的药物设计中的耐药性
- 批准号:
10642936 - 财政年份:2020
- 资助金额:
$ 70.23万 - 项目类别:
Integration of Evolution to Avoid Resistance in Structure Based Drug Design
整合进化以避免基于结构的药物设计中的耐药性
- 批准号:
10256048 - 财政年份:2020
- 资助金额:
$ 70.23万 - 项目类别:
Design of Protease Inhibitors to Target HTLV-1
针对 HTLV-1 的蛋白酶抑制剂的设计
- 批准号:
10057413 - 财政年份:2020
- 资助金额:
$ 70.23万 - 项目类别:
Structurally dissecting APOBEC3's for HIV-1 restriction
结构剖析 APOBEC3 的 HIV-1 限制
- 批准号:
9340247 - 财政年份:2016
- 资助金额:
$ 70.23万 - 项目类别:
Structurally dissecting APOBEC3's for HIV-1 restriction and beyond
从结构上剖析 APOBEC3 的 HIV-1 限制及其他限制
- 批准号:
10682566 - 财政年份:2016
- 资助金额:
$ 70.23万 - 项目类别:
Structurally dissecting APOBEC3's for HIV-1 restriction and beyond
从结构上剖析 APOBEC3 的 HIV-1 限制及其他限制
- 批准号:
10461788 - 财政年份:2016
- 资助金额:
$ 70.23万 - 项目类别:
Structurally dissecting APOBEC3's for HIV-1 restriction
结构剖析 APOBEC3 的 HIV-1 限制
- 批准号:
9769778 - 财政年份:2016
- 资助金额:
$ 70.23万 - 项目类别:
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