Retroviral intasome assembly and inhibition of DNA strand transfer
- S. Hare, Saumya Gupta, E. Valkov, A. Engelman, P. Cherepanov
- Biology, ChemistryNature
- 12 January 2010
The crystal structure of full-length integrase from the prototype foamy virus in complex with its cognate DNA is presented, defining the structural basis of retroviral DNA integration, and will allow modelling of the HIV-1 intasome to aid in the development of antiretroviral drugs.
HIV-1 Integrase Forms Stable Tetramers and Associates with LEDGF/p75 Protein in Human Cells*
- P. Cherepanov, G. Maertens, Z. Debyser
- BiologyJournal of Biological Chemistry
- 3 January 2003
The findings indicate that the minimal IN molecule in human cells is a homotetramer, suggesting that at least an octamer of IN is required to accomplish coordinated integration of both retroviral long terminal repeats and that LEDGF is a cellular factor involved in this process.
LEDGF/p75 Is Essential for Nuclear and Chromosomal Targeting of HIV-1 Integrase in Human Cells*
- G. Maertens, P. Cherepanov, Y. Engelborghs
- BiologyJournal of Biological Chemistry
- 29 August 2003
It is concluded that RNA interference-mediated knock-down of endogenous LEDGF/p75 expression abolished nuclear/chromosomal localization of IN and accounts for the karyophilic properties and chromosomal targeting of HIV-1 IN
LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration.
- Ming-chieh Shun, N. K. Raghavendra, A. Engelman
- BiologyGenes & Development
- 15 July 2007
Results reveal LEDGF/p75 as a critical targeting factor, commandeering lentiviruses from promoter- and/or CpG island-proximal pathways that are favored by other members of Retroviridae.
Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75.
- P. Cherepanov, A. Ambrosio, Shaila Rahman, T. Ellenberger, A. Engelman
- BiologyProceedings of the National Academy of Sciences…
- 29 November 2005
The crystal structure of the dimeric catalytic core domain of HIV-1 IN complexed to the IN-binding domain of LEDGF is reported, showing the backbone conformation of residues 168-171 from one monomer and a hydrophobic patch that is primarily comprised of alpha-helices 1 and 3 of the second IN monomer.
The mechanism of retroviral integration through X-ray structures of its key intermediates
- G. Maertens, S. Hare, P. Cherepanov
- Biology, ChemistryNature
- 18 October 2010
To establish productive infection, a retrovirus must insert a DNA replica of its genome into host cell chromosomal DNA. This process is operated by the intasome, a nucleoprotein complex composed of…
Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance
- S. Hare, Ann Vos, R. Clayton, J. Thuring, M. Cummings, P. Cherepanov
- BiologyProceedings of the National Academy of Sciences
- 28 October 2010
Improved resolution allowed us to refine the complete coordination spheres of the catalytic metal cations within the INSTI-bound intasome active site, and structures predict physical proximity and an interaction between HIV-1 IN mutant residues His148 and Ser/Ala140.
The structural biology of HIV-1: mechanistic and therapeutic insights
- A. Engelman, P. Cherepanov
- BiologyNature Reviews Microbiology
- 1 April 2012
Recent advances in HIV-1 structural biology are reviewed, focusing on the molecular mechanisms of viral replication and on the development of new therapeutics.
Structural Basis for Functional Tetramerization of Lentiviral Integrase
- S. Hare, F. Di Nunzio, A. Labeja, Jimin Wang, A. Engelman, P. Cherepanov
- Chemistry, BiologyPLoS Pathogens
- 1 July 2009
Two crystal structures containing the N-terminal and the catalytic core domains of maedi-visna virus IN in complex with the IN binding domain of the common lentiviral integration co-factor LEDGF reveal that the dimer-of-dimers architecture of the IN tetramer is stabilized by swapping N- terminal domains between the inner pair of monomers poised to execute catalytic function.
Identification of an Evolutionarily Conserved Domain in Human Lens Epithelium-derived Growth Factor/Transcriptional Co-activator p75 (LEDGF/p75) That Binds HIV-1 Integrase*
- P. Cherepanov, E. Devroe, P. Silver, A. Engelman
- BiologyJournal of Biological Chemistry
- 19 November 2004
This work used biochemical and bioinformatic approaches to define the domain organization of LEDGF/p75 and shows that the protein contains a pair of evolutionarily conserved domains, assuming about 35% of its sequence.
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