We propose to establish the Pittsburgh Center for HIV Protein Interactions (PCHPI), an interdisciplinary center that will specialize in developing methodologies and tools for deriving spatial atomic and cellular level structures of protein-interaction networks and for following the temporal sequence of key events after virus- cell fusion and before HIV genome integration (immediate, post-entry events). The PCHPI will bring scientists and facilities of the highest caliber together for elucidating the interactions of HIV proteins with host cell factors and will provide methodologies and tools to the HIV community at large. By accomplishing the proposed aims, the PCHPI will provide insight into an important area of HIV pathogenesis and open doors for exploring and developing alternative anti-HIV strategies. The center will integrate cellular imaging, biochemistry, and structural biology approaches and aims to: 1) Engage virologists, cell biologists, and structural biologists in a collaborative effort toward understanding HIV-host protein interactions and their structures; 2) Develop a framework for computationally predicting functionally important cellular interaction partners for HIV proteins and for experimentally validating in cells, that identified HIV-cellular protein interactions are relevant to HIV pathogenesis; 3) Establish a protein production core for HIV-host protein complexes using bacterial and eukaryotic expression systems; 4) Establish NMR and X-ray crystallography screening and structure determination cores for HIV accessory/regulatory proteins and their host protein complexes; and 5) Develop a robust HIV and cellular imaging program that combines cryo-electron tomography with cellular and single particle imaging methodologies. Results provided by the proposed research are expected to have major implications in the global fight against AIDS, still considered an incurable disease that afflicts 40 million individuals to date, and new therapeutic strategies and novel drug targets to combat the spread of infection is still a pressing need. Identifying and characterizing atomic structures of key interactions and pivotal events in the immediate post entry stage of the viral lifecycle will open new avenues in this endeavor. ? ? OVERALL ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
1P50GM082251-01
Application #
7340998
Study Section
Special Emphasis Panel (ZRG1-AARR-A (40))
Program Officer
Basavappa, Ravi
Project Start
2007-08-27
Project End
2012-07-31
Budget Start
2007-08-27
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$3,506,291
Indirect Cost
Name
University of Pittsburgh
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Varlakhanova, Natalia V; Alvarez, Frances J D; Brady, Tyler M et al. (2018) Structures of the fungal dynamin-related protein Vps1 reveal a unique, open helical architecture. J Cell Biol 217:3608-3624
Ning, Jiying; Zhong, Zhou; Fischer, Douglas K et al. (2018) Truncated CPSF6 Forms Higher-Order Complexes That Bind and Disrupt HIV-1 Capsid. J Virol 92:
Himes, Benjamin A; Zhang, Peijun (2018) emClarity: software for high-resolution cryo-electron tomography and subtomogram averaging. Nat Methods 15:955-961
Balasubramaniam, Muthukumar; Zhou, Jing; Addai, Amma et al. (2018) PF74 Inhibits HIV-1 Integration by Altering The Composition of the Preintegration Complex. J Virol :
Lu, Manman; Sarkar, Sucharita; Wang, Mingzhang et al. (2018) 19F Magic Angle Spinning NMR Spectroscopy and Density Functional Theory Calculations of Fluorosubstituted Tryptophans: Integrating Experiment and Theory for Accurate Determination of Chemical Shift Tensors. J Phys Chem B 122:6148-6155
Kraus, Jodi; Gupta, Rupal; Yehl, Jenna et al. (2018) Chemical Shifts of the Carbohydrate Binding Domain of Galectin-3 from Magic Angle Spinning NMR and Hybrid Quantum Mechanics/Molecular Mechanics Calculations. J Phys Chem B 122:2931-2939
Quinn, Caitlin M; Wang, Mingzhang; Polenova, Tatyana (2018) NMR of Macromolecular Assemblies and Machines at 1 GHz and Beyond: New Transformative Opportunities for Molecular Structural Biology. Methods Mol Biol 1688:1-35
Hadden, Jodi A; Perilla, Juan R (2018) All-atom virus simulations. Curr Opin Virol 31:82-91
Yan, Junpeng; Shun, Ming-Chieh; Hao, Caili et al. (2018) HIV-1 Vpr Reprograms CLR4DCAF1 E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection. MBio 9:
Dick, Robert A; Zadrozny, Kaneil K; Xu, Chaoyi et al. (2018) Inositol phosphates are assembly co-factors for HIV-1. Nature 560:509-512

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