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|Integrase Zinc binding domain|
|SCOP2||1wjb / SCOPe / SUPFAM|
|Integrase core domain|
|SCOP2||2itg / SCOPe / SUPFAM|
|Integrase DNA binding domain|
|SCOP2||1ihw / SCOPe / SUPFAM|
Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage integrases (recombinases) used in biotechnology, such as λ phage integrase, as discussed in site-specific recombination.
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]
- 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), with all three domains being important for multimerisation and viral DNA binding. 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.
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.[non-primary source needed]
Function and mechanism
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 of which depends on the activity of the chromosomal locus hosting the provirus.
Vis-a-vis mechanism, known retroviral INs 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 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 (in contrast to Ser/Tyr recombinase-catalyzed reactions.
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). The second integrase inhibitor, elvitegravir, was approved in the U.S. in August 2012.
- Beck BJ, Freudenreich O, Worth JL (2010-01-01). "26 - Patients with Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome". In Stern TA, Fricchione GL, Cassem NH, Jellinek MS (eds.). Massachusetts General Hospital Handbook of General Hospital Psychiatry (Sixth ed.). Saint Louis: W.B. Saunders. pp. 353–370. doi:10.1016/b978-1-4377-1927-7.00026-1. ISBN 978-1-4377-1927-7.
- 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, et al. (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. Lay summary – Reuters.
- See the PDB-101 link at the end of the article for the overall assembly.
- Morales-Ramirez JO, Teppler H, Kovacs C, Steigbigel RT, Cooper D, Liporace RL, et al. (November 2005). Abstract LBPS1/6: Antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor. ART-Naïve HIV-infected Patients. 10th European AIDS Conference. Dublin, Ireland. pp. 17–20. Archived from the original on 2006-10-29.
- Savarino A (December 2006). "A historical sketch of the discovery and development of HIV-1 integrase inhibitors". Expert Opinion on Investigational Drugs. 15 (12): 1507–22. doi:10.1517/13543722.214.171.1247. PMID 17107277. S2CID 207475472.
- "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, et al. (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): 2439–2448. doi:10.1016/S0140-6736(12)60917-9. PMID 22748591. S2CID 24183976.