Cyclin Box Structure of the P-TEFb Subunit Cyclin T1 Derived from a Fusion Complex with EIAV Tat

Anand, K.; Schulte, Antje; Fujinaga, Koh; Scheffzek, Klaus; Geyer, Matthias

doi:10.1016/j.jmb.2007.04.077

Cited by 34 publications

(43 citation statements)

References 55 publications

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“…In the absence of TAR RNA, cyclin T1 formed crystals with an electron density observed for residues 8-263, but no electron density was observed for EIAV Tat. This clearly indicated that cyclin T1 alone could not induce a stable conformation in Tat [288]. In the tripartite TAR RNA-cyclin T1-EIAV Tat complex (see Fig.…”

Section: Tatmentioning

confidence: 89%

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Protein intrinsic disorder as a flexible armor and a weapon of HIV-1

Xue

Mizianty

Kurgan

et al. 2011

Cell. Mol. Life Sci.

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Many proteins and protein regions are disordered in their native, biologically active states. These proteins/regions are abundant in different organisms and carry out important biological functions that complement the functional repertoire of ordered proteins. Viruses, with their highly compact genomes, small proteomes, and high adaptability for fast change in their biological and physical environment utilize many of the advantages of intrinsic disorder. In fact, viral proteins are generally rich in intrinsic disorder, and intrinsically disordered regions are commonly used by viruses to invade the host organisms, to hijack various host systems, and to help viruses in accommodation to their hostile habitats and to manage their economic usage of genetic material. In this review, we focus on the structural peculiarities of HIV-1 proteins, on the abundance of intrinsic disorder in viral proteins, and on the role of intrinsic disorder in their functions.

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Section: Tatmentioning

confidence: 89%

“…There are, however, known crystal structures of several complexes that contain Tat fragments. For example, an X-ray structure of the EIAV Tat in complex with cyclin T1 and TAR was reported [288]. Here, a 57-residue segment of EIAV Tat (residues 22-78) was fused via a flexible linker to the cyclin box domain of human cyclin T1.…”

Section: Tatmentioning

confidence: 99%

Protein intrinsic disorder as a flexible armor and a weapon of HIV-1

Xue

Mizianty

Kurgan

et al. 2011

Cell. Mol. Life Sci.

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“…In a previous study, we conducted in silico screening of compounds targeting a site containing the TRM of human CycT1 fused with EIAV Tat (PDB ID: 2PK2) (34). Using this system, we identified three compounds that inhibited HIV-1 replication in acutely infected cells at submicromolar concentrations (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Inhibitors of Human Immunodeficiency Virus Type 1 Replication by In Silico Screening Targeting Cyclin T1/Tat Interaction

Hamasaki

Okamoto

Baba

2013

Antimicrob Agents Chemother

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Human immunodeficiency virus type 1 (HIV-1) transcription is essential for viral replication and the only step for viral genome amplification. Cyclin T1 (CycT1) interacts with HIV-1 Tat and transactivation-responsive (TAR) RNA, leading to the activation of viral transcription through the hyperphosphorylation of RNA polymerase II (RNAPII). Thus, the CycT1/Tat/TAR RNA interaction represents a novel target for inhibition of HIV-1 replication. In this study, we conducted in silico screening of compounds targeting the CycT1/Tat/TAR RNA complex and found that two structurally related compounds (C1 and C2) had high docking scores for a model of the complex. These compounds proved inhibitory to HIV-1 replication in tumor necrosis factor alphastimulated chronically infected cells. In addition, C3, a derivative of C1 and C2, was found to be a more potent inhibitor of HIV-1 replication in chronically infected cells. C3 also inhibited HIV-1 replication in acutely infected cells. The compound could suppress Tat-mediated HIV-1 long terminal repeat-driven gene expression and phosphorylation of RNAPII through inhibition of Tat binding to CycT1. Furthermore, the docking pose of C3 was defined by analyses for its in silico docking energy and in vitro antiviral activity, which indicates that C3 interacts with Tat-binding amino acids of CycT1. Thus, a series of compounds described herein are novel inhibitors of HIV-1 transcription through inhibition of CycT1/Tat interaction.

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“…This is presumably because the precise mechanism by which these cyclins activate the kinase activity of their corresponding Cdks is not fully understood. In order to clarify the structurefunction relationship of CycT, which is critical for development of effective dominant negative CycT1 mutants, we have previously determined the crystal structure of the cyclin box region of CycT1 (Anand et al, 2007). The resultant three-dimensional structure indicated that CycT1 shares structural similarities with other cyclins (Anand et al, 2007).…”

mentioning

confidence: 99%

“…In order to clarify the structurefunction relationship of CycT, which is critical for development of effective dominant negative CycT1 mutants, we have previously determined the crystal structure of the cyclin box region of CycT1 (Anand et al, 2007). The resultant three-dimensional structure indicated that CycT1 shares structural similarities with other cyclins (Anand et al, 2007). These results suggest that certain functional motifs are well-conserved among cyclin molecules, although there is wide sequence diversity among them.…”

mentioning

confidence: 99%

Dominant negative mutant cyclin T1 proteins that inhibit HIV transcription by forming a kinase inactive complex with Tat

Jadlowsky

Nojima

Okamoto

et al. 2008

Journal of General Virology

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Transcription of the human immunodeficiency virus type 1 (HIV) requires the interaction of the cyclin T1 (CycT1) subunit of a host cellular factor, the positive transcription elongation factor b (P-TEFb), with the viral Tat protein, at the transactivation response element (TAR) of nascent transcripts. Because of this virus-specific interaction, CycT1 may potentially serve as a target for the development of anti-HIV therapies. Here we report the development of a mutant CycT1 protein, containing three threonine-to-alanine substitutions in the linker region between two of the cyclin boxes, which displays a potent dominant negative effect on HIV transcription. Investigation into the inhibitory mechanism revealed that this mutant CycT1 interacted with Tat and the cyclin-dependent kinase 9 (Cdk9) subunit of P-TEFb, but failed to stimulate the Cdk9 kinase activity critical for elongation. This mutant CycT1 protein may represent a novel class of specific inhibitors of HIV transcription which could lead to development of new antiviral therapies.

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Cyclin Box Structure of the P-TEFb Subunit Cyclin T1 Derived from a Fusion Complex with EIAV Tat

Cited by 34 publications

References 55 publications

Protein intrinsic disorder as a flexible armor and a weapon of HIV-1

Protein intrinsic disorder as a flexible armor and a weapon of HIV-1

Identification of Novel Inhibitors of Human Immunodeficiency Virus Type 1 Replication by In Silico Screening Targeting Cyclin T1/Tat Interaction

Dominant negative mutant cyclin T1 proteins that inhibit HIV transcription by forming a kinase inactive complex with Tat

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