Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: A model for viral DNA binding

Chen, Julian C.-H.; Krucinski, J.; Miercke, Larry J. W.; Finer-Moore, J.; Tang, A.H.; Leavitt, Andrew D.; Stroud, Rhonda M.

doi:10.1073/pnas.150220297

Cited by 385 publications

(463 citation statements)

References 48 publications

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“…For further details see text. Single domain crystallographic or NMR structures for IN were previously available for the CCD and the other two individual domains [199][200][201][202] as are two-domain structures for the CCD with either of the other two [203,204]. A full-length IN structure is a long-sought but still unrealized goal.…”

Section: Targeting Lentiviral Vectorsmentioning

confidence: 99%

Integrase, LEDGF/p75 and HIV replication

Poeschla

2008

Cell. Mol. Life Sci.

115

104

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HIV integrates a DNA copy of its genome into a host cell chromosome in each replication cycle. The essential DNA cleaving and joining chemistry of integration is known, but there is less understanding of the process as it occurs in a cell, where two complex and dynamic macromolecular entities are joined: the viral pre-integration complex and chromatin. Among implicated cellular factors, much recent attention has coalesced around LEDGF/p75, a nuclear protein that may act as a chromatin docking factor or receptor for lentiviral pre-integration complexes. LEDGF/p75 tethers HIV integrase to chromatin, protects it from degradation, and strongly influences the genome-wide pattern of HIV integration. Depleting the protein from cells and/or over-expressing its integrase-binding domain blocks viral replication. Current goals are to establish the underlying mechanisms and to determine whether this knowledge can be exploited for antiviral therapy or for targeting lentiviral vector integration in human gene therapy.

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Section: Targeting Lentiviral Vectorsmentioning

confidence: 99%

Integrase, LEDGF/p75 and HIV replication

Poeschla

2008

Cell. Mol. Life Sci.

115

104

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“…We list only the representative proteins of the protein families, which are colicin E9 (ColE9), 34 the periplasmic nuclease Vvn, 22 the HNH homing endonuclease I-HmuI, 35 the His-Cys box endonuclease I-PpoI, 18 the endonucleases such as Serratia nuclease, 17 CAD/DFF40, 32 the T4 Endo VII, 20 and HIV integrase (IN). 36 The lengths of the intervening sequence between the two ␤-strands vary from 2 to 39. The structures of the ␤␤␣-metal binding motifs of these proteins are shown in Figure 3.…”

Section: Results and Discussion The ␤␤␣-Metal Motifmentioning

confidence: 99%

“…The identified structural motif is located in the catalytic core domain of HIV IN. 36 Two of the three catalytic residues 36 of HIV IN, that is, D64 and E152, are located in this motif, while the third one (D116) is in the vicinity of the motif. Although we did not find a divalent metal ion in the center of the motif in the crystal structures of HIV IN, we did find a phosphate group (PO 4 Ϫ ) in 1K6Y, which is close to the supposed metal-binding site.…”

Section: Results and Discussion The ␤␤␣-Metal Motifmentioning

confidence: 99%

The fragment transformation method to detect the protein structural motifs

Lin

Chen

et al. 2006

Proteins

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To identify functional structural motifs from protein structures of unknown function becomes increasingly important in recent years due to the progress of the structural genomics initiatives. Although certain structural patterns such as the Asp-His-Ser catalytic triad are easy to detect because of their conserved residues and stringently constrained geometry, it is usually more challenging to detect a general structural motifs like, for example, the ␤␤␣-metal binding motif, which has a much more variable conformation and sequence. At present, the identification of these motifs usually relies on manual procedures based on different structure and sequence analysis tools. In this study, we develop a structural alignment algorithm combining both structural and sequence information to identify the local structure motifs. We applied our method to the following examples: the ␤␤␣-metal binding motif and the treble clef motif. The ␤␤␣-metal binding motif plays an important role in nonspecific DNA interactions and cleavage in host defense and apoptosis. The treble clef motif is a zinc-binding motif adaptable to diverse functions such as the binding of nucleic acid and hydrolysis of phosphodiester bonds. Our results are encouraging, indicating that we can effectively identify these structural motifs in an automatic fashion. Our method may provide a useful means for automatic functional annotation through detecting structural motifs associated with particular functions. Proteins 2006;63:636 -643.

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“…Figure 2 illustrates the dimeric atomic structure of the NTD with the CCD [10] (Fig. 2B) and the structure of the CCD in association with the CTD [11] (Fig. 2C).…”

Section: Integrase Structurementioning

confidence: 99%

“…Zinc binding residues (purple) and catalytic residues (red) are highlighted. B & C. Integrase crystal structures of the CCD + NTD [10] (PDB code: 1K6Y) and of the CCD + CTD [11] (PDB code: 1EX4). There is no published structure of the full-length integrase.…”

Section: Approaches To Inhibit Viral Integrationmentioning

confidence: 99%

Mechanisms and inhibition of HIV integration

Marchand

Johnson

Семенова

et al. 2006

Drug Discovery Today: Disease Mechanisms

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HIV integrase is required for viral replication and a rationale target for antiretroviral therapies. Integrase inhibitors are potentially complementary to current treatments. This review focuses on the mechanisms of HIV integration. The roles of viral and cellular co-factors during pre-integration complex (PIC) formation and integration are reviewed. The biochemical mechanisms of integration, integrase structures and approaches to inhibit integration are described.

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Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: A model for viral DNA binding

Cited by 385 publications

References 48 publications

Integrase, LEDGF/p75 and HIV replication

Integrase, LEDGF/p75 and HIV replication

The fragment transformation method to detect the protein structural motifs

Mechanisms and inhibition of HIV integration

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