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97  structures 83  species 6  interactions 266  sequences 38  architectures

Family: Integrase_Zn (PF02022)

Summary: Integrase Zinc binding domain

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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
Identifiers
SymbolIntegrase_Zn
PfamPF02022
InterProIPR003308
SCOPe1wjb / SUPFAM
Integrase core domain
PDB 1c1a EBI.jpg
Crystal structure of the RSV two-domain integrase.
Identifiers
Symbolrve
PfamPF00665
Pfam clanCL0219
InterProIPR001584
SCOPe2itg / SUPFAM
Integrase DNA binding domain
PDB 1c1a EBI.jpg
Crystal structure of the RSV two-domain integrase.
Identifiers
SymbolIN_DBD_C
PfamPF00552
InterProIPR001037
SCOPe1ihw / SUPFAM

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

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

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 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.[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

  1. ^ 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.
  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. ^ 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.
  4. ^ See the PDB-101 link at the end of the article for the overall assembly.
  5. ^ "Scientists say crack HIV/AIDS puzzle for drugs". Reuters. January 31, 2010.
  6. ^ 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
  7. ^ 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.
  8. ^ "FDA approves drug that fights HIV in new way - CNN.com". CNN. October 12, 2007. Retrieved May 5, 2010.
  9. ^ 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

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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 Zinc 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. This domain is the amino-terminal domain zinc binding domain. The central domain is the catalytic domain PF00665. The carboxyl terminal domain is a DNA binding domain PF00552.

Literature references

  1. Cai M, Zheng R, Caffrey M, Craigie R, Clore GM, Gronenborn AM; , Nat Struct Biol 1997;4:567-577.: Solution structure of the N-terminal zinc binding domain of HIV-1 integrase. PUBMED:9228950 EPMC:9228950


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR003308

Retroviral integrase mediates integration of a DNA copy of the viral genome into the host chromosome. Integrase is composed of three domains: an N-terminal zinc binding domain, a central catalytic core and a C-terminal DNA-binding domain [PUBMED:11743009, PUBMED:11101216]. Often found as part of the POL polyprotein.

Gene Ontology

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Domain organisation

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RP75
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(21)
Full
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(38173)
NCBI
(34187)
Meta
(0)
RP15
(58)
RP35
(82)
RP55
(234)
RP75
(268)
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  Seed
(21)
Full
(266)
Representative proteomes UniProt
(38173)
NCBI
(34187)
Meta
(0)
RP15
(58)
RP35
(82)
RP55
(234)
RP75
(268)
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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

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Curation View help on the curation process

Seed source: PSI-BLAST 1wjb
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Bateman A
Number in seed: 21
Number in full: 266
Average length of the domain: 37.70 aa
Average identity of full alignment: 41 %
Average coverage of the sequence by the domain: 7.01 %

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 21.7 21.7
Trusted cut-off 21.9 21.8
Noise cut-off 21.6 21.6
Model length: 38
Family (HMM) version: 19
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Archea Archea Eukaryota Eukaryota
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Viroids Viroids Unclassified sequence Unclassified sequence

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Interactions

There are 6 interactions for this family. More...

Integrase_Zn LEDGF rve rve MHC_I LEDGF

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 Integrase_Zn domain has been found. There are 97 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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