Solution structure of the N-terminal zinc binding domain of HIV-1 integrase

Cai, Mengli; Zheng, Ronglan; Caffrey, Michael; Craigie, Robert; Clore, G. Marius; Gronenborn, Angela M.

doi:10.1038/nsb0797-567

Cited by 328 publications

(315 citation statements)

References 60 publications

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“…For further details see text. Single domain crystallographic or NMR structures for IN were previously available for the CCD and the other two individual domains [199][200][201][202] as are two-domain structures for the CCD with either of the other two [203,204]. A full-length IN structure is a long-sought but still unrealized goal.…”

Section: Targeting Lentiviral Vectorsmentioning

confidence: 99%

Integrase, LEDGF/p75 and HIV replication

Poeschla

2008

Cell. Mol. Life Sci.

113

104

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HIV integrates a DNA copy of its genome into a host cell chromosome in each replication cycle. The essential DNA cleaving and joining chemistry of integration is known, but there is less understanding of the process as it occurs in a cell, where two complex and dynamic macromolecular entities are joined: the viral pre-integration complex and chromatin. Among implicated cellular factors, much recent attention has coalesced around LEDGF/p75, a nuclear protein that may act as a chromatin docking factor or receptor for lentiviral pre-integration complexes. LEDGF/p75 tethers HIV integrase to chromatin, protects it from degradation, and strongly influences the genome-wide pattern of HIV integration. Depleting the protein from cells and/or over-expressing its integrase-binding domain blocks viral replication. Current goals are to establish the underlying mechanisms and to determine whether this knowledge can be exploited for antiviral therapy or for targeting lentiviral vector integration in human gene therapy.

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Section: Targeting Lentiviral Vectorsmentioning

confidence: 99%

Integrase, LEDGF/p75 and HIV replication

Poeschla

2008

Cell. Mol. Life Sci.

113

104

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“…The mutation F185K markedly improved solubility of the central IN catalytic core domain to over 25 mg͞ml and led to its crystal structure (12,13). Structures of the individual N-terminal (14,15) and C-terminal domains (16)(17)(18) have been determined by NMR. Like the catalytic core domain, each isolated terminal domain dimerizes in solution.…”

mentioning

confidence: 99%

Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: A model for viral DNA binding

Chen

Krucinski

Miercke

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

384

445

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“…Crystallographic or NMR structural data are available for each of the individual domains (11)(12)(13)(14)(15). In addition, two-domain crystal structures [either the core and C-terminal domains (16), or N-terminal and the core domains (17) of HIV-1 IN] have been recently determined.…”

mentioning

confidence: 99%

Identification of an inhibitor-binding site to HIV-1 integrase with affinity acetylation and mass spectrometry

Shkriabai

Patil

Hess

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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We report a methodology that combines affinity acetylation with MS analysis for accurate mapping of an inhibitor-binding site to a target protein. For this purpose, we used a known HIV-1 integrase inhibitor containing aryl di-O-acetyl groups (Acetylated-Inhibitor). In addition, we designed a control compound (Acetylated-Control) that also contained an aryl di-O-acetyl group but did not inhibit HIV-1 integrase. Examination of the reactivity of these compounds with a model peptide library, which collectively contained all 20 natural amino acids, revealed that aryl di-O-acetyl compounds effectively acetylate Cys, Lys, and Tyr residues. Acetylated-Inhibitor and Acetylated-Control exhibited comparable chemical reactivity with respect to these small peptides. However, these two compounds differed markedly in their interactions with HIV-1 integrase. In particular, Acetylated-Inhibitor specifically acetylated K173 at its inhibitory concentration (3 M) whereas this site remained unrecognized by Acetylated-Control. Our data enabled creation of a detailed model for the integrase:Acetylated-Inhibitor complex, which indicated that the inhibitor selectively binds at an architecturally critical region of the protein. The methodology reported herein has a generic application for systems involving a variety of ligand-protein interactions.H IV-1 encodes three enzymes that are essential for virus replication: reverse transcriptase, protease, and integrase (IN). To date, only the first two proteins have been exploited as therapeutic targets. The continuing emergence of new HIV-1 variants resistant to current treatments, together with cytotoxicity problems, makes the search for new anti-HIV-1 drugs imperative. HIV-1 IN is an attractive antiviral drug target that has no known human counterparts. Furthermore, the use of a common active site for 3Ј end processing and DNA strand transfer constrain the range of mutations that can contribute to drug resistance without compromising catalytic activity.HIV-1 IN catalyzes integration of the viral DNA, made by reverse transcription, into the host chromosome in a two-step reaction (reviewed in ref. 1). In the first step, called 3Ј processing, two nucleotides are removed at each 3Ј end of the viral DNA. In the next step, called DNA strand transfer, concerted transesterification reactions integrate the viral DNA ends into the host genome. In vivo, the enzyme acts in the context of a large nucleoprotein complex termed the ''preintegration complex'' (PIC). A number of viral proteins and host factors assemble within the PIC to orchestrate the integration process (2-10).HIV-1 IN is composed of three distinct structural and functional domains: the N-terminal domain (residues 1-50), which contains the HHCC zinc-binding motif; the core domain (residues 51-212), which contains the catalytic site; and the Cterminal domain (residues 213-270), which is thought to provide a platform for DNA binding. Crystallographic or NMR structural data are available for each of the individual domains (11-15). In addition,...

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Solution structure of the N-terminal zinc binding domain of HIV-1 integrase

Cited by 328 publications

References 60 publications

Integrase, LEDGF/p75 and HIV replication

Integrase, LEDGF/p75 and HIV replication

Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: A model for viral DNA binding

Identification of an inhibitor-binding site to HIV-1 integrase with affinity acetylation and mass spectrometry

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