Crystal structure of the catalytic domain of avian sarcoma virus integrase

Bujacz, G.; Jaskólski, M.; Alexandratos, Jerry; Wlodawer, Alexander; Merkel, George; Katz, Richard A.; Skalka, Anna Marie

doi:10.1016/s1080-8914(96)80042-1

Cited by 9 publications

(13 citation statements)

References 27 publications

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“…The core domain (domain IIa) of MuA transposase (Rice & Mizuuchi, 1995) and the corresponding domain of HIV-1 integrase (Dyda et al 1994) share remarkable structural similarity: while almost every loop of the phage protein is larger, essentially all secondary structural elements of the two proteins can be superimposed. The structure of the ASV integrase (Bujacz et al 1995; not shown) is similar to that of the HIV integrase. RNaseH (E. coli protein (Yang et al 1990) is shown; the HIV protein is similar) and E. coli RuvC endonuclease (Ariyoshi et al 1994) also share the arrangement of the central mixed b sheet and several a helices surrounding it.…”

Section: K Mizuuchimentioning

confidence: 90%

“…Structural information is available for the core domains of the phage Mu transposase (Rice & Mizuuchi 1995), and two retroviral integrase proteins (those of HIV-1 and ASV, Dyda et al 1994;Bujacz et al 1995). The phage and retroviral proteins exhibit remarkable structural similarity, despite poor primary sequence conservation, and many other transposase proteins are expected to share the same basic structure of the catalytic core.…”

Section: K Mizuuchimentioning

confidence: 99%

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Polynucleotidyl transfer reactions in site‐specific DNA recombination

1997

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Site-specific DNA rearrangement reactions are widespread among organisms. They are used, for example, by vertebrates to boost immune response diversity, and in turn by parasitic organisms to evade the host immune system by surface antigen switching. Parasitic genetic elements ubiquitous to most organisms invade new host genomic sites by a variety of types of site-specific recombination. Polynucleotidyl transfer reactions are central to these DNA recombination reactions. The recombinase of each reaction system that 'catalyses' such chemical reactions at specific DNA sites are apparently designed to accomplish unique DNA geometrical specificity, or delicate control over the extent or direction of the reaction, with the sacrifice of protein turnover. Here we discuss our current understanding of several issues that relate to the polynucleotidyl transfer steps in several of the better studied site-specific recombination reactions.

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Section: K Mizuuchimentioning

confidence: 90%

Section: K Mizuuchimentioning

confidence: 99%

Polynucleotidyl transfer reactions in site‐specific DNA recombination

1997

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“…The structures were aligned on the core of the Tn5 inhibitor protein with the program OVRLAP (71). The coordinates for the ASV and HIV-1 integrases, and MU transposase core structures were obtained from the Brookhaven Protein Data Bank (accession numbers 1VSD, 1BIU, and 1ITG, respectively (10,21,26,44)). …”

Section: Comparison Of Transposase/integrase Catalytic Domains-mentioning

confidence: 99%

The Three-dimensional Structure of a Tn5Transposase-related Protein Determined to 2.9-Å Resolution

Davies

Braam

Reznikoff

et al. 1999

Journal of Biological Chemistry

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Transposon Tn5 employs a unique means of self-regulation by expressing a truncated version of the transposase enzyme that acts as an inhibitor. The inhibitor protein differs from the full-length transposase only by the absence of the first 55 N-terminal amino acid residues. It contains the catalytic active site of transposase and a C-terminal domain involved in protein-protein interactions. The three-dimensional structure of Tn5 inhibitor determined to 2.9-Å resolution is reported here. A portion of the protein fold of the catalytic core domain is similar to the folds of human immunodeficiency virus-1 integrase, avian sarcoma virus integrase, and bacteriophage Mu transposase. The Tn5 inhibitor contains an insertion that extends the ␤-sheet of the catalytic core from 5 to 9 strands. All three of the conserved residues that make up the "DDE" motif of the active site are visible in the structure. An arginine residue that is strictly conserved among the IS4 family of bacterial transposases is present at the center of the active site, suggesting a catalytic motif of "DDRE." A novel C-terminal domain forms a dimer interface across a crystallographic 2-fold axis. Although this dimer represents the structure of the inhibited complex, it provides insight into the structure of the synaptic complex.Transposition is a process in which a defined DNA sequence, called a transposable element, moves from one location to a second location on the same or another chromosome. Transposable elements occur widely in nature and include the simple insertion sequences or composite transposons of bacteria, certain bacteriophages, transposons, and retrotransposons of eukaryotic cells and retroviruses such as HIV-1.1 Originally described by McClintock (1) in a series of elegant experiments of controlling elements in maize, transposons have been found in all phyla studied to date, including humans. These mobile genetic elements are likely to have played a role in genome evolution and continue to shuffle antibiotic resistance traits among bacteria today (for a general review, see Ref.2). In eukaryotic species, transposons are not only numerous but also very promiscuous and are known to cause chromosome mutations. Also, the DNA cleavage reactions involved in immunoglobulin gene rearrangement have been shown to occur via a transposition mechanism (3).Achieving a molecular and structural understanding of transposition has been a formidable challenge in part because of the complexity of the process. Transposition is initiated by the binding of a transposable element-encoded protein called a transposase to specific DNA sequences located at or near the ends of the element. Next, the DNA-bound transposase oligomerizes to form a synaptic nucleoprotein complex. Thereafter cleavage of one or both strands at the transposon ends occurs where the exact cleavage sites are a property of the specific element (4, 5). The initial strand cleavage reaction is believed to occur via nucleophilic attack of an activated water molecule on the phosphodiester bond at th...

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“…2B). Retroviral integrase CCDs in the vast majority of cases crystallize as a homodimer with a large dimeric interface (43,140) (reviewed in 77), and the Lys185 side-chain composed part of the HIV-1 integrase CCD/ F185K interface (Fig. 2B).…”

Section: Integrase Domain Structuresmentioning

confidence: 99%

“…The mutation however rendered HIV-1 replication-defective, which was attributed to pleiotropic defects at the steps of virus particle assembly and reverse transcription (42). The CCD from the alpharetrovirus avian-sarcoma leukosis virus (ASLV) integrase was sufficiently soluble to permit its crystallization in the absence of solubility-enhancing mutations (140).…”

Section: Integrase Domain Structuresmentioning

confidence: 99%

Retroviral Integrase Structure and DNA Recombination Mechanism

Engelman

Cherepanov

2014

Microbiol Spectr

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SUMMARYDue to the importance of human immunodeficiency virus type 1 (HIV-1) integrase as a drug target, the biochemistry and structural aspects of retroviral DNA integration have been the focus of intensive research during the past three decades. The retroviral integrase enzyme acts on the linear double-stranded viral DNA product of reverse transcription. Integrase cleaves specific phosphodiester bonds near the viral DNA ends during the 3′ processing reaction. The enzyme then uses the resulting viral DNA 3′-OH groups during strand transfer to cut chromosomal target DNA, which simultaneously joins both viral DNA ends to target DNA 5′-phosphates. Both reactions proceed via direct transesterification of scissile phosphodiester bonds by attacking nucleophiles: a water molecule for 3′ processing, and the viral DNA 3′-OH for strand transfer. X-ray crystal structures of prototype foamy virus integrase-DNA complexes revealed the architectures of the key nucleoprotein complexes that form sequentially during the integration process and explained the roles of active site metal ions in catalysis. X-ray crystallography furthermore elucidated the mechanism of action of HIV-1 integrase strand transfer inhibitors, which are currently used to treat AIDS patients, and provided valuable insights into the mechanisms of viral drug resistance.

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Crystal structure of the catalytic domain of avian sarcoma virus integrase

Cited by 9 publications

References 27 publications

Polynucleotidyl transfer reactions in site‐specific DNA recombination

Polynucleotidyl transfer reactions in site‐specific DNA recombination

The Three-dimensional Structure of a Tn5Transposase-related Protein Determined to 2.9-Å Resolution

Retroviral Integrase Structure and DNA Recombination Mechanism

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