Summary: Integrase DNA binding domain
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| Integrase Zinc binding domain | |||||||||
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 solution structure of the n-terminal zn binding domain of hiv-1 integrase (e form), nmr, 38 structures | |||||||||
| Identifiers | |||||||||
| Symbol | Integrase_Zn | ||||||||
| Pfam | PF02022 | ||||||||
| InterPro | IPR003308 | ||||||||
| SCOPe | 1wjb / SUPFAM | ||||||||
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| Integrase core domain | |||||||||
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 Crystal structure of the RSV two-domain integrase. | |||||||||
| Identifiers | |||||||||
| Symbol | rve | ||||||||
| Pfam | PF00665 | ||||||||
| Pfam clan | CL0219 | ||||||||
| InterPro | IPR001584 | ||||||||
| SCOPe | 2itg / SUPFAM | ||||||||
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| Integrase DNA binding domain | |||||||||
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Crystal structure of the RSV two-domain integrase. | |||||||||
| Identifiers | |||||||||
| Symbol | IN_DBD_C | ||||||||
| Pfam | PF00552 | ||||||||
| InterPro | IPR001037 | ||||||||
| SCOPe | 1ihw / SUPFAM | ||||||||
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Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its DNA (genetic information) into that of the host cell it infects.[citation needed] Retroviral INs are distinct from phage integrases, such as λ phage integrase, as discussed in site-specific recombination.[not verified in body]
The macromolecular complex of an IN macromolecule bound to the ends of the viral DNA ends has been referred to as the intasome; IN is a key component in this and the retroviral pre-integration complex.[clarification needed][1]
Structure
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All retroviral IN proteins contain three canonical domains, connected by flexible linkers:[2][non-primary source needed]
- an N-terminal HH-CC zinc-binding domain (a three-helical bundle stabilised by coordination of a Zn(II) cation)
- a catalytic core domain (RNaseH fold)
- a C-terminal DNA-binding domain (SH3 fold).
Crystal and NMR structures of the individual domains and 2-domain constructs of integrases from HIV-1, HIV-2, SIV, and Rous Sarcoma Virus (RSV) have been reported, with the first structures determined in 1994.[citation needed] Biochemical data and structural data suggest that retroviral IN functions as a tetramer (dimer-of-dimers), with all three domains being important for multimerisation and viral DNA binding.[citation needed] In addition, several host cellular proteins have been shown to interact with IN to facilitate the integration process: e.g., the host factor, human chromatin-associated protein LEDGF, tightly binds HIV IN and directs the HIV pre-integration complex towards highly expressed genes for integration.[citation needed]
Human foamy virus (HFV), an agent harmless to humans, has an integrase similar to HIV IN and is therefore a model of HIV IN function; a 2010 crystal structure of the HFV integrase assembled on viral DNA ends has been determined.[3][non-primary source needed][4][5]
Function and mechanism
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Integration occurs following production of the double-stranded viral DNA by the viral RNA/DNA-dependent DNA polymerase reverse transcriptase.[citation needed]
The main function of IN is to insert the viral DNA into the host chromosomal DNA, a step that is essential for HIV replication.[citation needed] Integration is a "point of no return"" for the cell,{{cite quote"" which becomes a permanent carrier of the viral genome (provirus).[citation needed] Integration is in part responsible for the persistence of retroviral infections.[citation needed] After integration, the viral gene expression and particle production may take place immediately or at some point in the future, the timing of which depends on the activity of the chromosomal locus hosting the provirus.[citation needed]
Vis-a-vis mechanism, known retroviral INs catalyzes two reactions:[citation needed]
- 3'-processing, in which two or three nucleotides are removed from one or both 3' ends of the viral DNA to expose an invariant CA dinucleotide at both 3'-ends of the viral DNA.
- the strand transfer reaction, in which the processed 3' ends of the viral DNA are covalently ligated to host chromosomal DNA.
Both reactions are catalysed in the same active site, and involve transesterification that does not involve a covalent protein-DNA intermediate[citation needed] (in contrast to Ser/Tyr recombinase-catalyzed reactions.[citation needed]
In HIV
HIV integrase is a 32 kDa protein produced from the C-terminal portion of the Pol gene product, and is an attractive target for new anti-HIV drugs.[citation needed]
In November 2005, data from a phase 2 study of an investigational HIV integrase inhibitor, MK-0518, demonstrated that the compound has potent antiviral activity.[6][7] On October 12, 2007, the Food and Drug Administration (U.S.) approved the integrase inhibitor Raltegravir (MK-0518, brand name Isentress).[8] The second integrase inhibitor, elvitegravir, was approved in the U.S. in August 2012.[9]
See also
References
- ^ Masuda, T. (January 1, 2011). "Non-Enzymatic Functions of Retroviral Integrase: The Next Target for Novel Anti-HIV Drug Development". Frontiers in Microbiology. 2: 210. doi:10.3389/fmicb.2011.00210. PMC 3192317. PMID 22016749.
- ^ Lodi PJ, Ernst JA, Kuszewski J, Hickman AB, Engelman A, Craigie R, Clore GM, Gronenborn AM (August 1995). "Solution structure of the DNA binding domain of HIV-1 integrase". Biochemistry. 34 (31): 9826–33. doi:10.1021/bi00031a002. PMID 7632683.
- ^ Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P (March 2010). "Retroviral intasome assembly and inhibition of DNA strand transfer". Nature. 464 (7286): 232–6. Bibcode:2010Natur.464..232H. doi:10.1038/nature08784. PMC 2837123. PMID 20118915.
- ^ See the PDB-101 link at the end of the article for the overall assembly.
- ^ "Scientists say crack HIV/AIDS puzzle for drugs". Reuters. January 31, 2010.
- ^ Morales-Ramirez JO, Teppler H, Kovacs C, et al. Antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in ART-naïve HIV-1 infected patients. Program and abstracts of the 10th European AIDS Conference; November 17–20, 2005; Dublin, Ireland. Abstract LBPS1/6. Online summary: http://clinicaloptions.com/HIV/Conference%20Coverage/Dublin%202005/Capsules/LBPS1-6.aspx
- ^ Savarino A (December 2006). "A historical sketch of the discovery and development of HIV-1 integrase inhibitors". Expert Opin Investig Drugs. 15 (12): 1507–22. doi:10.1517/13543784.15.12.1507. PMID 17107277.
- ^ "FDA approves drug that fights HIV in new way - CNN.com". CNN. October 12, 2007. Retrieved May 5, 2010.
- ^ Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D, Gallant JE, Liu HC, Zhong L, Yale K, White K, Kearney BP, Szwarcberg J, Quirk E, Cheng AK (June 2012). "Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks". Lancet. 379 (9835): 2439–48. doi:10.1016/S0140-6736(12)60917-9. PMID 22748591.
External links
- PDB-101 Molecule of the Month: 135 HIV Integrase
- Integrases at the US National Library of Medicine Medical Subject Headings (MeSH)
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Integrase DNA binding domain Provide feedback
Integrase mediates integration of a DNA copy of the viral genome into the host chromosome. Integrase is composed of three domains. The amino-terminal domain is a zinc binding domain. The central domain is the catalytic domain PF00665. This domain is the carboxyl terminal domain that is a non-specific DNA binding domain [1].
Literature references
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Lodi PJ, Ernst JA, Kuszewski J, Hickman AB, Engelman A, Craigie R, Clore GM, Gronenborn AM; , Biochemistry 1995;34:9826-9833.: Solution structure of the DNA binding domain of HIV-1 integrase. PUBMED:7632683 EPMC:7632683
External database links
| HOMSTRAD: | integrase |
| SCOP: | 1ihw |
This tab holds annotation information from the InterPro database.
InterPro entry IPR001037
Integrase comprises three domains capable of folding independently and whose three-dimensional structures are known. However, the manner in which the N-terminal, catalytic core, and C-terminal domains interact in the holoenzyme remains obscure. Numerous studies indicate that the enzyme functions as a multimer, minimally a dimer. The integrase proteins from Human immunodeficiency virus 1 (HIV-1) and Avian sarcoma virus (have been studied most carefully with respect to the structural basis of catalysis. Although the active site of avian virus integrase does not undergo significant conformational changes on binding the required metal cofactor, that of HIV-1 does. This active site-mediated conformational change in HIV-1 reorganises the catalytic core and C-terminal domains and appears to promote an interaction that is favourable for catalysis [PUBMED:10384242].
Retroviral integrase is synthesised as part of the POL polyprotein that contains; an aspartyl protease, a reverse transcriptase, RNase H and integrase. POL polyprotein undergoes specific enzymatic cleavage to yield the mature proteins. The presence of retrovirus integrase-related gene sequences in eukaryotes is known. Bacterial transposases involved in the transposition of the insertion sequence also belong to this group.
HIV-1 integrase catalyses the incorporation of virally derived DNA into the human genome. This unique step in the virus life cycle provides a variety of points for intervention and hence is an attractive target for the development of new therapeutics for the treatment of AIDS [PUBMED:9161051]. Substrate recognition by the retroviral integrase enzyme is critical for retroviral integration. To catalyse this recombination event, integrase must recognise and act on two types of substrates, viral DNA and host DNA, yet the necessary interactions exhibit markedly different degrees of specificity [PUBMED:10384243].
Gene Ontology
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
| Molecular function | nucleic acid binding (GO:0003676) |
Domain organisation
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Alignments
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| Seed (9) |
Full (80) |
Representative proteomes | UniProt (38679) |
NCBI (31616) |
Meta (0) |
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| RP15 (53) |
RP35 (71) |
RP55 (79) |
RP75 (82) |
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| HTML | |||||||||
| PP/heatmap | 1 | ||||||||
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| Seed (9) |
Full (80) |
Representative proteomes | UniProt (38679) |
NCBI (31616) |
Meta (0) |
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| RP15 (53) |
RP35 (71) |
RP55 (79) |
RP75 (82) |
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| Raw Stockholm | |||||||||
| Gzipped | |||||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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Curation and family details
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Curation
| Seed source: | SCOP |
| Previous IDs: | integrase; Integrase; |
| Type: | Domain |
| Sequence Ontology: | SO:0000417 |
| Author: |
Bateman A 
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| Number in seed: | 9 |
| Number in full: | 80 |
| Average length of the domain: | 47.30 aa |
| Average identity of full alignment: | 35 % |
| Average coverage of the sequence by the domain: | 4.74 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 50 | ||||||||||||
| Family (HMM) version: | 21 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Structures
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the IN_DBD_C domain has been found. There are 45 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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