Summary: Integrase core domain
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Integrase Edit Wikipedia article
|Integrase Zinc binding domain|
solution structure of the n-terminal zn binding domain of hiv-1 integrase (e form), nmr, 38 structures
|Integrase core domain|
crystal structure of rsv two-domain integrase
|Integrase DNA binding domain|
crystal structure of rsv two-domain integrase
Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that enables its genetic material to be integrated into the DNA of the infected cell. Retroviral INs are not to be confused with phage integrases, such as λ phage integrase (Int) (see site-specific recombination).
IN is a key component in the retroviral pre-integration complex (PIC).
All retroviral IN proteins contain three canonical domains, connected by flexible linkers:
- 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.
Biochemical data and structural data suggest that retroviral IN functions as a tetramer (dimer-of-dimers). All three domains are important for multimerisation and viral DNA binding. Early in 2010, scientists solved the crystal structure of IN from prototype foamy virus (PFV) assembled on viral DNA ends.
In addition, several host cellular proteins have been shown to interact with IN to facilitate the integration process. Human chromatin-associated protein LEDGF, which tightly binds HIV IN and directs HIV PIC towards highly-expressed genes for integration, is an example of such a host factor.
Integration occurs following production of the double-stranded viral DNA by the viral RNA/DNA-dependent DNA polymerase reverse transcriptase.
The main function of IN is to insert the viral DNA into the host chromosomal DNA, a step that is essential for HIV replication. Integration is a point of no return for the cell, which becomes a permanent carrier of the viral genome (provirus). Integration is in part responsible for the persistence of retroviral infections. After integration, the viral gene expression and particle production may take place immediately or at some point in the future. The timing, it is presumed, depends on the activity of the chromosomal locus hosting the provirus.
Retroviral IN catalyzes two reactions:
- 3'-processing, in which two or three nucleotides are removed from one or both 3' ends of the viral DNA to expose the invariant CA dinucleotides 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 the host chromosomal DNA.
Both reactions are catalysed by the same active site and occur via transesterification, without a covalent protein-DNA intermediate, in contrast to reactions catalysed by Ser and Tyr recombinases (see site specific recombination).
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. On October 12, 2007, the Food and Drug Administration (U.S.) approved the integrase inhibitor Raltegravir (MK-0518, brand name Isentress TM). The second integrase inhibitor, elvitegravir, was approved in the U.S. in August 2012.
- 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.
- "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:10.1517/135437188.8.131.527. 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.
- 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. doi:10.1038/nature08784. PMC 2837123. PMID 20118915.
- Selwood T, Jaffe EK (March 2012). "Dynamic dissociating homo-oligomers and the control of protein function". Arch. Biochem. Biophys. 519 (2): 131–43. doi:10.1016/j.abb.2011.11.020. PMID 22182754.
Integrase core 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 PF02022. This domain is the central catalytic domain. The carboxyl terminal domain that is a non-specific DNA binding domain PF00552. The catalytic domain acts as an endonuclease when two nucleotides are removed from the 3' ends of the blunt-ended viral DNA made by reverse transcription. This domain also catalyses the DNA strand transfer reaction of the 3' ends of the viral DNA to the 5' ends of the integration site .
Dyda F, Hickman AB, Jenkins TM, Engelman A, Craigie R, Davies DR; , Science 1994;266:1981-1986.: Crystal structure of the catalytic domain of HIV-1 integrase: similarity to other polynucleotidyl transferases [see comments] PUBMED:7801124 EPMC:7801124
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001584
Integrase comprises three domains capable of folding independently and whose three-dimensional structures are known. However, the manner in which the N-terminal, catalytic, 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 (ASV) have been studied most carefully with respect to the structural basis of catalysis. Although the active site of ASV 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 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].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Biological process||DNA integration (GO:0015074)|
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a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
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This clan includes a diverse set of nucleases that share a similar structure to Ribonuclease H.
The clan contains the following 46 members:CAF1 DDE_1 DDE_2 DDE_3 DDE_5 DDE_Tnp_1 DDE_Tnp_1_2 DDE_Tnp_1_3 DDE_Tnp_1_4 DDE_Tnp_1_5 DDE_Tnp_1_6 DDE_Tnp_1_7 DDE_Tnp_2 DDE_Tnp_4 DDE_Tnp_IS1 DDE_Tnp_IS1595 DDE_Tnp_IS240 DDE_Tnp_IS66 DDE_Tnp_ISAZ013 DDE_Tnp_ISL3 DNA_pol_A_exo1 DNA_pol_B_exo1 DNA_pol_B_exo2 DUF2779 DUF3882 DUF4152 DUF458 Maelstrom MULE NurA Piwi Plant_tran Pox_A22 RNase_H RNase_H_2 RNase_HII RNase_T RuvC rve rve_2 rve_3 RVT_3 Transposase_1 Transposase_mut UPF0236 Ydc2-catalyt
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Curation and family details
|Seed source:||Pfam-B_10 (release 2.1)|
|Number in seed:||230|
|Number in full:||47519|
|Average length of the domain:||111.40 aa|
|Average identity of full alignment:||27 %|
|Average coverage of the sequence by the domain:||21.34 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||21|
|Download:||download the raw HMM for this family|
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There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 rve domain has been found. There are 244 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 seqence.
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