Summary: Integrase core 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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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
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 [1].
Literature references
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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
Internal database links
| SCOOP: | DDE_2 DDE_3 DDE_Tnp_IS1595 DDE_Tnp_IS240 DDE_Tnp_IS66 gag_pre-integrs Integrase_H2C2 RT_RNaseH rve_2 rve_3 RVT_1 |
| Similarity to PfamA using HHSearch: | DDE_3 DDE_Tnp_IS240 |
External database links
| HOMSTRAD: | rvintegrase |
| SCOP: | 2itg |
This tab holds annotation information from the InterPro database.
InterPro entry IPR001584
The retroviral integrase is the enzyme responsible for the insertion of a DNA copy of the viral genome into host DNA, an essential step in the replication cycle of viruses [PUBMED:9759480]. Integrases comprise three functional and structural domains: the central core domain, which contains the catalytic residues, an N-terminal zinc finger and a C-terminal DNA binding domain[PUBMED:10384240].
The integrase catalytic domain catalyzes a series of reactions to integrate the viral genome into a host chromosome. In the first step, it removes two 3' end nucleotides from each strand of the linear viral DNA, leaving overhanging CA-OH ends. In the second step, the processed 3' ends are covalently joined to the 5' ends of the target DNA. In the third step, which probably involves additional cellular enzymes, unpaired nucleotides at the viral 5' ends are removed and the ends are joined to the target site 3' ends, generating an integrated provirus flanked by five base-pair direct repeats of the target site DNA [PUBMED:7526778].
The crystal structure of the catalytic domain shows a dimeric structure, with each monomer containing a five-stranded beta-sheet and six alpha-helices [PUBMED:7801124]. This fold is characteristic of the polynucleotidyltransferase superfamily whose members include RNase H, the bacteriophage Mu transposase, and the E. coli Holliday junction resolving enzyme, RuvC [PUBMED:8696976]. The catalytic domain of integrase contains the DD35E triad motif. As in other DNA-binding proteins containing this motif, these acidic residues coordinate a divalent Mg2+ in the resting enzyme. Substituting any one of these residues abolishes both processing and integration activities of integrase.
The integrase catalytic domain is also found in various transposase proteins.
Gene Ontology
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) |
Domain organisation
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Pfam Clan
This family is a member of clan RNase_H (CL0219), which has the following description:
This clan includes a diverse set of nucleases that share a similar structure to Ribonuclease H.
The clan contains the following 64 members:
Arena_ncap_C 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 Dimer_Tnp_Tn5 DNA_pol_A_exo1 DNA_pol_B_exo1 DNA_pol_B_exo2 DNA_pol_P_Exo DUF1258 DUF2779 DUF3882 DUF4152 DUF5051 DUF99 Endonuclease_5 KDZ Maelstrom MULE NurA OrfB_IS605 Piwi Plant_tran Plavaka Pox_A22 RNase_H RNase_H_2 RNase_HII RNase_T RNaseH_like RT_RNaseH RT_RNaseH_2 RuvC RuvC_1 rve rve_2 rve_3 RVT_3 Taq-exonuc Terminase_3C Terminase_6C Transposase_1 Transposase_21 Transposase_mut UPF0236 UvrC_HhH_N Ydc2-catalytAlignments
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
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| Seed (76) |
Full (34282) |
Representative proteomes | UniProt (167170) |
NCBI (348722) |
Meta (2455) |
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| RP15 (8431) |
RP35 (19112) |
RP55 (31217) |
RP75 (48390) |
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| PP/heatmap | 1 | ||||||||
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
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| Seed (76) |
Full (34282) |
Representative proteomes | UniProt (167170) |
NCBI (348722) |
Meta (2455) |
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|---|---|---|---|---|---|---|---|---|---|
| RP15 (8431) |
RP35 (19112) |
RP55 (31217) |
RP75 (48390) |
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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: | Pfam-B_10 (release 2.1) |
| Previous IDs: | none |
| Type: | Domain |
| Sequence Ontology: | SO:0000417 |
| Author: |
Bateman A 
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| Number in seed: | 76 |
| Number in full: | 34282 |
| Average length of the domain: | 100.30 aa |
| Average identity of full alignment: | 19 % |
| Average coverage of the sequence by the domain: | 17.86 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 102 | ||||||||||||
| Family (HMM) version: | 27 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Interactions
There are 7 interactions for this family. More...
IN_DBD_C Integrase_Zn IN_DBD_C LEDGF rve LEDGF Integrase_ZnStructures
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 571 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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