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Integrase DNA binding domain

crystal structure of rsv two-domain integrase

Identifiers

Symbol

IN_DBD_C

Pfam

PF00552

InterPro

IPR001037

SCOP

1ihw

SUPERFAMILY

1ihw

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

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).

Structure[edit]

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)^[1]

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.^[2]

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.

Function[edit]

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 IN[edit]

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.^[3]^[4] On October 12, 2007, the Food and Drug Administration (U.S.) approved the integrase inhibitor Raltegravir (MK-0518, brand name Isentress ^TM).^[5] The second integrase inhibitor, elvitegravir, was approved in the U.S. in August 2012.^[6]

The crystal structure of human foamy virus integrase has been examined successfully.^[7]

This protein may use the morpheein model of allosteric regulation.^[8]

References[edit]

^ 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:10.1517/13543784.15.12.1507. 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.
^ 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.

External links[edit]

Integrases at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. インテグラーゼ阻害剤の薬理学 pharmacology of integrase inhibitors
2. HIV抗レトロウイルス療法に関する臨床試験：インテグラーゼ阻害剤 clinical trials of hiv antiretroviral therapy integrase inhibitors
3. 妊娠時の抗レトロウイルス剤：侵入阻害剤およびインテグラーゼ阻害剤 antiretroviral medications in pregnancy entry and integrase inhibitors
4. ヌクレオシド系逆転写酵素阻害剤の薬理学 pharmacology of nucleoside reverse transcriptase inhibitors
5. HIV抗レトロウイルス療法に関する臨床試験：開発中の薬剤 clinical trials of hiv antiretroviral therapy agents in advanced stages of development

English Journal

Impact of reclaimed water irrigation on antibiotic resistance in public parks, Beijing, China.

Wang FH, Qiao M, Lv ZE, Guo GX, Jia Y, Su YH, Zhu YG.SourceState Key Lab of Urban and Regional Ecology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
Environmental pollution (Barking, Essex : 1987).Environ Pollut.2014 Jan;184:247-53. doi: 10.1016/j.envpol.2013.08.038. Epub 2013 Sep 24.
The abundance and distribution of antibiotics and antibiotic resistance genes (ARGs) in soils from six parks using reclaimed water in Beijing, China, were characterized. Three classes of commonly used antibiotics (tetracycles, quinolones, and sulfonamides) were analyzed by liquid chromatography-tand
PMID 24071635

Traditional Chinese medicine application in HIV: an in silico study.

Huang HJ, Jian YR, Chen CY.Sourcea Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources , China Medical University , Taichung , 40402 , Taiwan .
Journal of biomolecular structure & dynamics.J Biomol Struct Dyn.2014 Jan;32(1):1-12. doi: 10.1080/07391102.2012.745168. Epub 2012 Dec 20.
Viral infection by human immunodeficiency virus (HIV) requires integration of viral DNA with host DNA which involves the binding of HIV integrase (IN) with its co-factor lens epithelium-derived growth factor (LEDGF/p75). Since disrupted binding of IN with LEDGF/p75 inhibits proliferation of HIV, inh
PMID 23252879

Approaches to the synthesis of a novel, anti-HIV active integrase inhibitor.

Okello M, Nishonov M, Singh P, Mishra S, Mangu N, Seo B, Gund M, Nair V.SourceCenter for Drug Discovery and College of Pharmacy, University of Georgia, Athens, GA 30602, USA. vnair@uga.edu.
Organic & biomolecular chemistry.Org Biomol Chem.2013 Dec 7;11(45):7852-8. doi: 10.1039/c3ob41728j. Epub 2013 Oct 7.
The novel HIV-1 integrase inhibitor 1, discovered in our laboratory, exhibits potent anti-HIV activity against a diverse set of HIV-1 isolates and also against HIV-2 and SIV. In addition, this compound displays low cellular cytotoxicity and possesses a favorable in vitro drug interaction profile wit
PMID 24100441

Japanese Journal

Use of a Hexasubstituted Benzene Scaffold in the Development of Multivalent HIV-1 Integrase Inhibitors

Tupchiangmai Wipa,Choksakulporn Saowanaporn,Tewtrakul Supinya [他]
Chemical and pharmaceutical bulletin 62(8), 754-763, 2014-08
NAID 40020136534

Targeted gene integration using the combination of a sequence-specific DNA-binding protein and phiC31 integrase.

Nakanishi Hideyuki,Higuchi Yuriko,Yamashita Fumiyoshi,Hashida Mitsuru
Journal of biotechnology 186, 139-147, 2014-07-17
… PhiC31 integrase-based vectors can integrate therapeutic genes selectively into attP or pseudo-attP sites in genomes, but considerable numbers of pseudo-attP sites in human genomes exist inside endogenous gene-coding regions. … To avoid endogenous gene disruptions, we aimed to enhance the integration site-specificity of the phiC31 integrase-based vector using a sequence-specific DNA-binding protein containing Gal4 and LexA DNA-binding motifs. …
NAID 120005466731

Identification of a Novel Metallo-β-Lactamase VIM-28 Located within Unusual Arrangement of Class 1 Integron Structure in Pseudomonas aeruginosa Isolates from Egypt

El-Mahdy Taghrid S.
Japanese Journal of Infectious Diseases 67(5), 382-384, 2014
… Additional sequencing of integron revealed that the blaVIM-28 gene cassette had an unusual arrangement of class 1 integron structure, located directly downstream of the integrase gene "intI1" and oriented divergently from it. …
NAID 130004692239

Related Pictures

★リンクテーブル★

リンク元	「インテグラーゼ」「組込み酵素」
拡張検索	「HIV integrase inhibitor」「HIV-1 integrase」

「インテグラーゼ」

Integrase core domain
	; crystal structure of rsv two-domain integrase
Identifiers
Symbol	rve
Pfam	PF00665
Pfam clan	CL0219
InterPro	IPR001584
SCOP	2itg
SUPERFAMILY	2itg
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Integrase Zinc binding domain
	; 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
SCOP	1wjb
SUPERFAMILY	1wjb
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary