HARC Center: HIV Accessory and Regulatory Complexes

HARC 中心：HIV 辅助和调节复合体

• 批准号: 10229558
• 负责人: Nevan J Krogan
• 金额: $ 480.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-27 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229558
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Antibodies; Antiviral Agents; Biological; Biological Assay; Biology; CRISPR/Cas technology; Cell physiology; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Complement; Complex; Cryoelectron Microscopy; DNA; Detection; Development; Electron Microscopy; Ensure; Enzymes; Event; Evolution; Funding Opportunities; Genetic; Genetic Transcription; Genetic study; Goals; HIV; HIV-1; Host Defense; Human; In Vitro; Individual; Interdisciplinary Study; Intervention; Label; Laboratories; Lead; Learning; Life Cycle Stages; Light; Lipids; Mass Spectrum Analysis; Membrane; Membrane Lipids; Membrane Proteins; Methodology; Methods; Mission; Modeling; Molecular; Mutation; Nucleic Acids; Other Genetics; Pathogenesis; Pathway interactions; Patients; Peptides; Peroxidases; Pharmaceutical Preparations; Positive Transcriptional Elongation Factor B; Post-Translational Protein Processing; Program Development; Proteins; Proteomics; RNA; Regimen; Regulation; Research; Research Personnel; Residencies; Resolution; Resources; Roentgen Rays; Scientist; Seeds; Series; Sister; Source; Structure; System; T-Lymphocyte; TNFRSF5 gene; Techniques; Technology; Therapeutic; Therapeutic Intervention; Traction; Training; Ubiquitination; Validation; Viral; Virus; Work; X-Ray Crystallography; ascorbate; beamline; cofactor; cohort; data sharing; drug efficacy; flexibility; genetic approach; genetic information; genetic regulatory protein; improved; in vivo; innovation; insight; member; molecular imaging; nanodisk; nef Protein; new technology; next generation; novel; novel therapeutic intervention; outreach; programs; protein complex; protein expression; resistance mutation; rev Protein; scaffold; screening; structural biology; symposium; tat Protein; technology training; therapeutic target; titanium dioxide; tool; trafficking; treatment strategy; vif Gene Products; virology; virus genetics; vpu Protein

CENTERS FOR HIV/AIDS-RELATED STRUCTURAL BIOLOGY (P50) HARC CENTER: HIV ACCESSORY AND REGULATORY COMPLEXES OVERALL SUMMARY The HARC Center is an integrated program proposed by investigators whose overarching goal is to improve understanding of the interactions between HIV accessory and regulatory proteins and host cellular systems to enable eventual expansion of therapeutic approaches. There are currently no HIV therapeutics targeting any of the proteins on which the HARC Center is focused (HIV-1 Vif, Vpu, Nef, Tat and Rev proteins and their interacting viral and cellular partners). The scientific focus of the Center is on determining structures of these complexes, using an integrated Systems to Structure pipeline that includes (1) Discovery, through novel methods of functional proteomics and genetics being developed in the HARC Center, (2) Validation through breakthrough CRISPR methods in primary T cells as well as targeted in vivo and in vitro functional assays, and (3) Structure Determination using a synthesis of innovative structural techniques developed in the HARC Center to address the large, flexible, heterogeneous and sometimes membrane-associated systems we study. We are focused on two themes aimed at understanding the biological questions surrounding HIV replication and persistence in the host cell. These include how the virus counteracts host restriction mechanisms (Theme 1: “Counteracting”) and how the virus hijacks host systems for viral transcription and RNA export/trafficking to ensure continuation of the viral life cycle (Theme 2: “Hijacking”). The seven projects proposed here include: (1) Structure and Evolution of APOBEC3-Vif Interactions, (2) Regulation of Vif and Rewiring of Host Pathways, (3) The Multiple Functions of Vpu at the Membrane, (4) Nef Interaction Networks at the Membrane, (5) Tat-Host Transcription Complexes, (6) Structure and Dynamics of Rev and RNA-Host Complexes, and (7) Characterization of “Super Restriction Factors” and Prediction of Host-HIV Interfaces. The HARC Center projects are supported by an administrative core and seven technology cores essential for their completion: (1) Proteomic Approaches to HIV Function, (2) CRISPR in Primary Cells to Study HIV-Host Function, (3) Molecular Imaging Using Cryo-Electron Microscopy (EM), (4) Application and Development of Antibody Tools, (5) Integrative Modeling of HIV-Human Complexes, (6) X-ray Screening and Rapid Structure Determination, and (7) Membrane Protein Expression/Purification. We are committed to collaborating with Sister Centers and the HIV research community as well as training the next generation of investigators. We create and support opportunities including the Technology Training Residency to bring young investigators to learn in our Center's Cores, and we seed new research through the Collaborative Opportunity Fund, along with holding events such as seminars and an annual symposium.

艾滋病毒/艾滋病相关结构生物学中心（P50） HARC中心：HIV附件和调节复合物 总体汇总 HARC中心是由研究人员提出的一个综合项目，其总体目标是改善 了解HIV辅助蛋白和调节蛋白与宿主细胞系统之间的相互作用， 使治疗方法最终得以扩展。目前还没有针对任何 HARC中心关注的蛋白质（HIV-1 Vif、Vpu、Nef、达特和Rev蛋白质及其组合）中， 相互作用的病毒和细胞伴侣）。该中心的科学重点是确定这些结构 复杂，使用集成的系统结构管道，包括（1）发现，通过新的 HARC中心正在开发的功能蛋白质组学和遗传学方法，（2）通过 在原代T细胞中的突破性CRISPR方法以及靶向体内和体外功能测定，以及 (3)使用HARC开发的创新结构技术的合成进行结构测定 中心，以解决大型，灵活，异构，有时膜相关的系统，我们研究。 我们集中在两个主题，旨在了解围绕艾滋病毒复制的生物学问题 和在宿主细胞中的持久性。这些包括病毒如何抵消宿主的限制机制（主题 1：“抵消”）以及病毒如何劫持宿主系统进行病毒转录和RNA输出/运输 确保病毒生命周期的延续（主题2：“劫持”）。这里提出的七个项目 包括：（1）APOBEC 3-Vif相互作用的结构和进化，（2）Vif的调节和宿主的重新布线 途径，（3）Vpu在膜上的多种功能，（4）Nef在膜上的相互作用网络， (5)Tat-宿主转录复合物，（6）Rev和RNA-宿主复合物的结构和动力学，以及（7） “超级限制因子”的表征和宿主-HIV界面的预测。HARC中心 项目由一个行政核心和完成项目所必需的七个技术核心提供支持：（1） HIV功能的蛋白质组学方法，（2）在原代细胞中研究HIV宿主功能的CRISPR，（3） 使用冷冻电子显微镜（EM）的分子成像，（4）抗体工具的应用和开发， (5)HIV-人复合物的综合建模，（6）X射线筛选和快速结构测定， 和（7）膜蛋白表达/纯化。 我们致力于与姐妹中心和艾滋病毒研究界合作，并培训 下一代的调查员。我们创造和支持包括技术培训在内的机会 住院医生带来年轻的研究人员在我们中心的核心学习，我们通过种子新的研究， 合作机会基金，沿着举办研讨会和年度专题讨论会等活动。

项目成果

Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery.

• DOI: 10.1021/acs.jmedchem.0c02177
• 发表时间: 2021-05-27
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Kryštůfek R;Šácha P;Starková J;Brynda J;Hradilek M;Tloušt'ová E;Grzymska J;Rut W;Boucher MJ;Drąg M;Majer P;Hájek M;Řezáčová P;Madhani HD;Craik CS;Konvalinka J
• 通讯作者: Konvalinka J

IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV.

• DOI: 10.1126/science.1243640
• 发表时间: 2014-01-24
• 期刊: Science (New York, N.Y.)
• 作者: Monroe KM;Yang Z;Johnson JR;Geng X;Doitsh G;Krogan NJ;Greene WC
• 通讯作者: Greene WC

Evolution and functional cross-talk of protein post-translational modifications.

• DOI: 10.1002/msb.201304521
• 发表时间: 2013
• 期刊: MOLECULAR SYSTEMS BIOLOGY
• 影响因子: 9.9
• 作者: Beltrao, Pedro;Bork, Peer;Krogan, Nevan J.;van Noort, Vera
• 通讯作者: van Noort, Vera

GPS-Prot: a web-based visualization platform for integrating host-pathogen interaction data.

• DOI: 10.1186/1471-2105-12-298
• 发表时间: 2011-07-22
• 期刊: BMC bioinformatics
• 影响因子: 3
• 作者: Fahey ME;Bennett MJ;Mahon C;Jäger S;Pache L;Kumar D;Shapiro A;Rao K;Chanda SK;Craik CS;Frankel AD;Krogan NJ
• 通讯作者: Krogan NJ

Oligomeric viral proteins: small in size, large in presence.

• DOI: 10.1080/10409238.2016.1215406
• 发表时间: 2016-09
• 期刊: Critical reviews in biochemistry and molecular biology
• 影响因子: 6.5
• 作者: Jayaraman B;Smith AM;Fernandes JD;Frankel AD
• 通讯作者: Frankel AD