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Cellular cofactors of lentiviral integrase: from target validation to drug discovery.

Taltynov O, Desimmie BA, Demeulemeester J, Christ F, Debyser Z - Mol Biol Int (2012)

Bottom Line: The nuclear import factor transportin-SR2 (TRN-SR2) has been proposed as another interactor of HIV IN-mediating nuclear import of the virus.Using both proteins as examples, we will describe approaches to be taken to identify and validate novel cofactors as new antiviral targets.Finally, we will highlight recent advances in the design and the development of small-molecule inhibitors binding to the LEDGF/p75-binding pocket in IN (LEDGINs).

View Article: PubMed Central - PubMed

Affiliation: The Laboratory for Molecular Virology and Gene Therapy, KU Leuven, Leuven, Flanders, Belgium.

ABSTRACT
To accomplish their life cycle, lentiviruses make use of host proteins, the so-called cellular cofactors. Interactions between host cell and viral proteins during early stages of lentiviral infection provide attractive new antiviral targets. The insertion of lentiviral cDNA in a host cell chromosome is a step of no return in the replication cycle, after which the host cell becomes a permanent carrier of the viral genome and a producer of lentiviral progeny. Integration is carried out by integrase (IN), an enzyme playing also an important role during nuclear import. Plenty of cellular cofactors of HIV-1 IN have been proposed. To date, the lens epithelium-derived growth factor (LEDGF/p75) is the best studied cofactor of HIV-1 IN. Moreover, small molecules that block the LEDGF/p75-IN interaction have recently been developed for the treatment of HIV infection. The nuclear import factor transportin-SR2 (TRN-SR2) has been proposed as another interactor of HIV IN-mediating nuclear import of the virus. Using both proteins as examples, we will describe approaches to be taken to identify and validate novel cofactors as new antiviral targets. Finally, we will highlight recent advances in the design and the development of small-molecule inhibitors binding to the LEDGF/p75-binding pocket in IN (LEDGINs).

No MeSH data available.


Related in: MedlinePlus

Domain organization of HIV-1 IN and LEDGF/p75. (a) HIV-1 IN is composed of an N-terminal domain (NTD), a catalytic core domain (CCD), and a C-terminal domain (CTD). The CCD contains the catalytically essential DD(35)E motif and the hot spots for interaction with the IBD in LEDGF/p75. The Asp and Glu residues of the CCD coordinate one or two Mg2+ ions and are involved in 3′ processing and DNA strand-transfer activities. (b) LEDGF/p75 has several structural motifs involved in chromatin tethering and protein-protein interactions. The PWWP domain, the charged regions (CRs), and AT-hooks are involved in chromatin binding. The C-terminus contains the well-characterized IN binding domain (IBD) and acts as a protein interaction playground. Asp residue 366 critical for HIV-1 IN binding is indicated.
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fig1: Domain organization of HIV-1 IN and LEDGF/p75. (a) HIV-1 IN is composed of an N-terminal domain (NTD), a catalytic core domain (CCD), and a C-terminal domain (CTD). The CCD contains the catalytically essential DD(35)E motif and the hot spots for interaction with the IBD in LEDGF/p75. The Asp and Glu residues of the CCD coordinate one or two Mg2+ ions and are involved in 3′ processing and DNA strand-transfer activities. (b) LEDGF/p75 has several structural motifs involved in chromatin tethering and protein-protein interactions. The PWWP domain, the charged regions (CRs), and AT-hooks are involved in chromatin binding. The C-terminus contains the well-characterized IN binding domain (IBD) and acts as a protein interaction playground. Asp residue 366 critical for HIV-1 IN binding is indicated.

Mentions: In recent years, HIV-1 integrase (IN) joined the selection of important therapeutic targets to treat HIV infection (for a review see [22]). The enzyme orchestrates the insertion of the viral DNA into the host chromatin [23, 24]. HIV IN is a 32-kDa protein containing 3 canonical structural domains connected by flexible linkers: the N-terminal (NTD, residues 1–50), the catalytic core (CCD, residues 51–212), and the C-terminal domain (CTD, 213–270) (Figure 1(a)). All 3 domains are required for 3′ processing and DNA strand transfer. The solution structure of the N-terminal HHCC domain revealed a three-helix bundle stabilized by zinc [25]. The central catalytic core domain contains the DD(35)E motif conserved among retroviruses and retrotransposons. D64, D116, E152 residues coordinate 2 Mg2+ ions necessary for catalysis [26]. The C-terminal domain has a SH3-like fold [27]. Full-length HIV-1 IN is a multimeric enzyme and forms stable tetramers in solution [28].


Cellular cofactors of lentiviral integrase: from target validation to drug discovery.

Taltynov O, Desimmie BA, Demeulemeester J, Christ F, Debyser Z - Mol Biol Int (2012)

Domain organization of HIV-1 IN and LEDGF/p75. (a) HIV-1 IN is composed of an N-terminal domain (NTD), a catalytic core domain (CCD), and a C-terminal domain (CTD). The CCD contains the catalytically essential DD(35)E motif and the hot spots for interaction with the IBD in LEDGF/p75. The Asp and Glu residues of the CCD coordinate one or two Mg2+ ions and are involved in 3′ processing and DNA strand-transfer activities. (b) LEDGF/p75 has several structural motifs involved in chromatin tethering and protein-protein interactions. The PWWP domain, the charged regions (CRs), and AT-hooks are involved in chromatin binding. The C-terminus contains the well-characterized IN binding domain (IBD) and acts as a protein interaction playground. Asp residue 366 critical for HIV-1 IN binding is indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3420096&req=5

fig1: Domain organization of HIV-1 IN and LEDGF/p75. (a) HIV-1 IN is composed of an N-terminal domain (NTD), a catalytic core domain (CCD), and a C-terminal domain (CTD). The CCD contains the catalytically essential DD(35)E motif and the hot spots for interaction with the IBD in LEDGF/p75. The Asp and Glu residues of the CCD coordinate one or two Mg2+ ions and are involved in 3′ processing and DNA strand-transfer activities. (b) LEDGF/p75 has several structural motifs involved in chromatin tethering and protein-protein interactions. The PWWP domain, the charged regions (CRs), and AT-hooks are involved in chromatin binding. The C-terminus contains the well-characterized IN binding domain (IBD) and acts as a protein interaction playground. Asp residue 366 critical for HIV-1 IN binding is indicated.
Mentions: In recent years, HIV-1 integrase (IN) joined the selection of important therapeutic targets to treat HIV infection (for a review see [22]). The enzyme orchestrates the insertion of the viral DNA into the host chromatin [23, 24]. HIV IN is a 32-kDa protein containing 3 canonical structural domains connected by flexible linkers: the N-terminal (NTD, residues 1–50), the catalytic core (CCD, residues 51–212), and the C-terminal domain (CTD, 213–270) (Figure 1(a)). All 3 domains are required for 3′ processing and DNA strand transfer. The solution structure of the N-terminal HHCC domain revealed a three-helix bundle stabilized by zinc [25]. The central catalytic core domain contains the DD(35)E motif conserved among retroviruses and retrotransposons. D64, D116, E152 residues coordinate 2 Mg2+ ions necessary for catalysis [26]. The C-terminal domain has a SH3-like fold [27]. Full-length HIV-1 IN is a multimeric enzyme and forms stable tetramers in solution [28].

Bottom Line: The nuclear import factor transportin-SR2 (TRN-SR2) has been proposed as another interactor of HIV IN-mediating nuclear import of the virus.Using both proteins as examples, we will describe approaches to be taken to identify and validate novel cofactors as new antiviral targets.Finally, we will highlight recent advances in the design and the development of small-molecule inhibitors binding to the LEDGF/p75-binding pocket in IN (LEDGINs).

View Article: PubMed Central - PubMed

Affiliation: The Laboratory for Molecular Virology and Gene Therapy, KU Leuven, Leuven, Flanders, Belgium.

ABSTRACT
To accomplish their life cycle, lentiviruses make use of host proteins, the so-called cellular cofactors. Interactions between host cell and viral proteins during early stages of lentiviral infection provide attractive new antiviral targets. The insertion of lentiviral cDNA in a host cell chromosome is a step of no return in the replication cycle, after which the host cell becomes a permanent carrier of the viral genome and a producer of lentiviral progeny. Integration is carried out by integrase (IN), an enzyme playing also an important role during nuclear import. Plenty of cellular cofactors of HIV-1 IN have been proposed. To date, the lens epithelium-derived growth factor (LEDGF/p75) is the best studied cofactor of HIV-1 IN. Moreover, small molecules that block the LEDGF/p75-IN interaction have recently been developed for the treatment of HIV infection. The nuclear import factor transportin-SR2 (TRN-SR2) has been proposed as another interactor of HIV IN-mediating nuclear import of the virus. Using both proteins as examples, we will describe approaches to be taken to identify and validate novel cofactors as new antiviral targets. Finally, we will highlight recent advances in the design and the development of small-molecule inhibitors binding to the LEDGF/p75-binding pocket in IN (LEDGINs).

No MeSH data available.


Related in: MedlinePlus