Sandbox Reserved 1502

This Sandbox is Reserved from 06/12/2018, through 30/06/2019 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1480 through Sandbox Reserved 1543.

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3lpt - HIV integrase3lpt - HIV integrase

<StructureSection load='3lpt' size='340' side='right' caption='3lpt, resolution 2.00Å' scene=> 3lt is an integrase of the HIV, the Human Immunodeficiency Virus. An integrase is an enzyme produced by a retrovirus to integrate its genetic material into the DNA of the infected cell. It is one of three enzymes of HIV, the others being the Reverse Transcriptase and the Protease.

Structural highlightsStructural highlights

Ligands:	, , , , ,
NonStd Res:
Related:	1hyv, 3lpu
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

FunctionFunction

HIV integrase is an enzyme required for the integration of viral DNA into the host genome. The process of integration can be divided into two sequential reactions. In the first one, named 3'-processing, the enzyme removes di- or trinucleotides from viral DNA ends to expose 3′-hydroxyls attached to the invariant CA dinucleotides. The second step is the insertion of the processed 3′-viral DNA ends into the host chromosomal DNA by a trans-esterification reaction. This is the strand transfer.

Interaction with LEDGF/p75 and antiviralInteraction with LEDGF/p75 and antiviral

Research on HIV shows that the integrase uses a protein, the LEDGF/p75 cofactor, to ligate the preintegration complex to the DNA. Some recent experimental antiviral inhibits this interaction and unable the integrase to interact with the cofactor. Thus, the DNA wouldn’t be inserted into the genome of the cell.

StructureStructure

HIV-1 integrase is composed of three domains: the N-terminal (residues 1-49), the core domain (residues 50-212) and the C-terminal domain (residues 213-288). The core domain is responsible for the catalytic activity of the enzyme. It contains three acidic residues, the D,D-35-E motif which plays a key role in catalysis. The N-terminal domain includes the conserved HHCC motif, which binds zinc. The C-terminal domain is less well conserved. [1]

Structure and role of the core domain in the integrationStructure and role of the core domain in the integration

The three domain of the HIV integrase:

HIV Integrase sequence:

[2] Length:288, Mass (Da):32,199

[3]

Structure and role of the core domainStructure and role of the core domain

The catalytic core domain contains three acidic residues, the D,D-35-E motif, comprising residues Asp64, Asp116, and Glu152. By analogy with models of catalysis by DNA polymerases, it has been proposed that coordination of divalent metal ion to these residues plays a key role in catalysis. The catalytic residues Asp64, Asp116, and Glu152of HIV-1 integrase and their counterparts in the ASV structures are in close proximity, coordinate divalent metal ion, and define the active site. However, the residues comprising the active site region exhibit considerable flexibility, suggesting that binding of DNA substrate is required to impose the precise configuration of residues that are required for catalysis.

Structure and role of the N ter domainStructure and role of the N ter domain

The N-terminal domain of HIV-1 integrase contains a conserved pair of His and Cys residues, a motif similar to the zinc-coordinating residues of zinc fingers. This domain binds zinc but its structure is totally different from that of zinc fingers. It consists of a bundle of three α-helices. It has an SH3 fold, although there is no known functional relationship with the SH3 domains of other proteins.

Ligands:

Structure and role of the C ter domainStructure and role of the C ter domain

Structure and interaction with the antiviralStructure and interaction with the antiviral

The new experimental antiviral, here the (6-chloro-2-oxo-4-phenyl-1,2-dihydroquinoline-3-yl)acetic acid, interacts with the site with which . This site is situated in the core domain. The molecule then inhibits the interaction between the LEDGF/p75 cofactor and the integrase. The whole complex between the integrase and the cofactor is displayed on the Proteopedia page 2b4j.

HIVHIV

HIV stands for human immunodeficiency virus. It is a retrovirus virus that damages the cells in the immune system and weakens the ability to fight everyday infections and disease. Copied into DNA, HIV is inserted into the genome of the infected cell thanks to integrases. To replicate and diffuse himself it attacks the body’s immune system, specifically the CD4 cells (T cells), which help fight off infections. As soon as HIV enters an individual, it accumulates in these cells and forms reservoirs of latent viruses in a few days or even hours. These reservoirs persist for life.

No cure currently exists, but HIV can be controlled by using antiretroviral therapy or ART. It is a combination of antiretroviral drugs to maximally suppress the HIV virus and stop the progression of HIV disease. Before the introduction of ART in the mid-1990s, people with HIV could progress to AIDS in just a few years. Today, someone diagnosed with HIV and treated before the disease is far advanced can live nearly as long as someone who does not have HIV.[4]

Disease: AIDSDisease: AIDS

AIDS is the ultimate stage of infection with the human immunodeficiency virus. The word AIDS stands for Acquired Immunodeficiency Syndrome. People with AIDS get an increasing number of severe illnesses, called opportunistic infections, because of there damaged immune system. You are considered to have progressed to AIDS when the number of your CD4 cells falls below 200 cells per cubic millimeter of blood (200 cells/mm3). (In someone with a healthy immune system, CD4 counts are between 500 and 1,600 cells/mm3.) You are also considered to have progressed to AIDS if you develop one or more opportunistic illnesses, regardless of your CD4 count.[5]

See alsoSee also

http://proteopedia.org/wiki/index.php/2b4j :integrase ligated with the cofactor LEDGF/p75

ReferencesReferences

https://www.hiv.gov/hiv-basics/overview/about-hiv-and-aids/what-are-hiv-and-aids https://www-nature-com.scd-rproxy.u-strasbg.fr/articles/nchembio.370 https://www.uniprot.org/uniprot/Q76353#sequences http://pfam.xfam.org/family/rve http://pfam.xfam.org/protein/Q76353_9HIV1 https://www.rcsb.org/3d-view/3LPT/1 https://en.wikipedia.org/wiki/Diethylene_glycol https://microbewiki.kenyon.edu/index.php/HIV-1_Pre-Integration_Complex https://www.uniprot.org/uniprot/Q76353 https://www.rcsb.org/structure/3lpt http://proteopedia.org/wiki/index.php/Retroviral_Integrase http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=3lpt