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45  structures 56  species 3  interactions 80  sequences 28  architectures

Family: IN_DBD_C (PF00552)

Summary: Integrase DNA binding domain

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This is the Wikipedia entry entitled "Integrase". More...

Integrase Edit Wikipedia article

Integrase Zinc binding domain
PDB 1wjd EBI.jpg
solution structure of the n-terminal zn binding domain of hiv-1 integrase (e form), nmr, 38 structures
Symbol Integrase_Zn
Pfam PF02022
InterPro IPR003308
SCOP 1wjb
Integrase core domain
PDB 1c1a EBI.jpg
crystal structure of rsv two-domain integrase
Symbol rve
Pfam PF00665
Pfam clan CL0219
InterPro IPR001584
SCOP 2itg
Integrase DNA binding domain
PDB 1c1a EBI.jpg
crystal structure of rsv two-domain integrase
Symbol IN_DBD_C
Pfam PF00552
InterPro IPR001037
SCOP 1ihw

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). The complex of integrase bound to cognate viral DNA (vDNA) ends has been referred to as the intasome.[1]


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)[2]

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.[3]

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).


HIV Integrase shown in its full structure with its catalytic amino acids shown in ball and stick form.

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.

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.[4][5] On October 12, 2007, the Food and Drug Administration (U.S.) approved the integrase inhibitor Raltegravir (MK-0518, brand name Isentress).[6] The second integrase inhibitor, elvitegravir, was approved in the U.S. in August 2012.[7]

The crystal structure of human foamy virus integrase has been examined successfully.[8]

This protein may use the morpheein model of allosteric regulation.[9]

See also


  1. ^ Masuda, Takao (2011-01-01). "Non-enzymatic functions of retroviral integrase: the next target for novel anti-HIV drug development". Virology. 2: 210. doi:10.3389/fmicb.2011.00210. PMC 3192317Freely accessible. PMID 22016749. 
  2. ^ 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. 
  3. ^ "Scientists say crack HIV/AIDS puzzle for drugs". Reuters. January 31, 2010. 
  4. ^ 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:
  5. ^ 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. 
  6. ^ "FDA approves drug that fights HIV in new way -". CNN. October 12, 2007. Retrieved May 5, 2010. 
  7. ^ 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. 
  8. ^ 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 2837123Freely accessible. PMID 20118915. 
  9. ^ 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/ PMC 3298769Freely accessible. PMID 22182754. 

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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

  1. 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

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

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Domain organisation

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Seed source: SCOP
Previous IDs: integrase; Integrase;
Type: Domain
Sequence Ontology: SO:0000417
Author: Bateman A
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 View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.7 20.7
Trusted cut-off 21.9 20.8
Noise cut-off 20.2 18.3
Model length: 50
Family (HMM) version: 21
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Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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There are 3 interactions for this family. More...

IN_DBD_C rve rve


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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