scholarly journals Association of mitochondrial lysyl-tRNA synthetase with HIV-1 GagPol involves catalytic domain of the synthetase and transframe and integrase domains of Pol

2011 ◽  
Vol 27 (5) ◽  
pp. 381-382
Author(s):  
L. Kobbi ◽  
J. Dias ◽  
G. Octobre ◽  
M. Comisso ◽  
M. Kaminska ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Trna Synthetase ◽  
Hiv 1

Association of Mitochondrial Lysyl-tRNA Synthetase with HIV-1 GagPol Involves Catalytic Domain of the Synthetase and Transframe and Integrase Domains of Pol

2011 ◽  
Vol 410 (5) ◽  
pp. 875-886 ◽  
Author(s):  
Lydia Kobbi ◽  
Guillaume Octobre ◽  
José Dias ◽  
Martine Comisso ◽  
Marc Mirande
Keyword(s):  
Catalytic Domain ◽  
Trna Synthetase ◽  
Hiv 1

scholarly journals How HIV-1 Integrase Associates with Human Mitochondrial Lysyl-tRNA Synthetase

Viruses ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 1202 ◽  
Author(s):  
Xaysongkhame Phongsavanh ◽  
Noha Al-Qatabi ◽  
Mohammed Samer Shaban ◽  
Fawzi Khoder-Agha ◽  
Merwan El Asri ◽  
...  
Keyword(s):  
Structural Model ◽  
Catalytic Domain ◽  
Three Dimensional ◽  
Docking Simulation ◽  
Trna Synthetase ◽  
Amino Acid Residues ◽  
3D Architecture ◽  
Polyprotein Precursor ◽  
Viral Polyprotein ◽  
Hiv 1

Replication of human immunodeficiency virus type 1 (HIV-1) requires the packaging of tRNALys,3 from the host cell into the new viral particles. The GagPol viral polyprotein precursor associates with mitochondrial lysyl-tRNA synthetase (mLysRS) in a complex with tRNALys, an essential step to initiate reverse transcription in the virions. The C-terminal integrase moiety of GagPol is essential for its association with mLysRS. We show that integrases from HIV-1 and HIV-2 bind mLysRS with the same efficiency. In this work, we have undertaken to probe the three-dimensional (3D) architecture of the complex of integrase with mLysRS. We first established that the C-terminal domain (CTD) of integrase is the major interacting domain with mLysRS. Using the pBpa-photo crosslinking approach, inter-protein cross-links were observed involving amino acid residues located at the surface of the catalytic domain of mLysRS and of the CTD of integrase. In parallel, using molecular docking simulation, a single structural model of complex was found to outscore other alternative conformations. Consistent with crosslinking experiments, this structural model was further probed experimentally. Five compensatory mutations in the two partners were successfully designed which supports the validity of the model. The complex highlights that binding of integrase could stabilize the tRNALys:mLysRS interaction.

scholarly journals Inhibitory mechanism of reveromycin A at the tRNA binding site of a class I synthetase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Bingyi Chen ◽  
Siting Luo ◽  
Songxuan Zhang ◽  
Yingchen Ju ◽  
Qiong Gu ◽  
...  
Keyword(s):  
Binding Site ◽  
Catalytic Domain ◽  
Trna Synthetase ◽  
Rational Drug Design ◽  
Class I ◽  
Binding Assays ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Rational Drug ◽  
Trna Binding

AbstractThe polyketide natural product reveromycin A (RM-A) exhibits antifungal, anticancer, anti-bone metastasis, anti-periodontitis and anti-osteoporosis activities by selectively inhibiting eukaryotic cytoplasmic isoleucyl-tRNA synthetase (IleRS). Herein, a co-crystal structure suggests that the RM-A molecule occupies the substrate tRNAIle binding site of Saccharomyces cerevisiae IleRS (ScIleRS), by partially mimicking the binding of tRNAIle. RM-A binding is facilitated by the copurified intermediate product isoleucyl-adenylate (Ile-AMP). The binding assays confirm that RM-A competes with tRNAIle while binding synergistically with l-isoleucine or intermediate analogue Ile-AMS to the aminoacylation pocket of ScIleRS. This study highlights that the vast tRNA binding site of the Rossmann-fold catalytic domain of class I aminoacyl-tRNA synthetases could be targeted by a small molecule. This finding will inform future rational drug design.

scholarly journals HIV-1 Exploits a Dynamic Multi-aminoacyl-tRNA Synthetase Complex To Enhance Viral Replication

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Alice A. Duchon ◽  
Corine St. Gelais ◽  
Nathan Titkemeier ◽  
Joshua Hatterschide ◽  
Li Wu ◽  
...  
Keyword(s):  
Viral Replication ◽  
Nuclear Localization ◽  
Reverse Transcription ◽  
Transcriptase Inhibitor ◽  
Trna Synthetase ◽  
Mitogen Activated Protein Kinase ◽  
Heat Inactivation ◽  
Target Cells ◽  
Aminoacyl Trna Synthetase ◽  
Hiv 1

ABSTRACT A hallmark of retroviruses such as human immunodeficiency virus type 1 (HIV-1) is reverse transcription of genomic RNA to DNA, a process that is primed by cellular tRNAs. HIV-1 recruits human tRNALys3 to serve as the reverse transcription primer via an interaction between lysyl-tRNA synthetase (LysRS) and the HIV-1 Gag polyprotein. LysRS is normally sequestered in a multi-aminoacyl-tRNA synthetase complex (MSC). Previous studies demonstrated that components of the MSC can be mobilized in response to certain cellular stimuli, but how LysRS is redirected from the MSC to viral particles for packaging is unknown. Here, we show that upon HIV-1 infection, a free pool of non-MSC-associated LysRS is observed and partially relocalized to the nucleus. Heat inactivation of HIV-1 blocks nuclear localization of LysRS, but treatment with a reverse transcriptase inhibitor does not, suggesting that the trigger for relocalization occurs prior to reverse transcription. A reduction in HIV-1 infection is observed upon treatment with an inhibitor to mitogen-activated protein kinase that prevents phosphorylation of LysRS on Ser207, release of LysRS from the MSC, and nuclear localization. A phosphomimetic mutant of LysRS (S207D) that lacked the capability to aminoacylate tRNALys3 localized to the nucleus, rescued HIV-1 infectivity, and was packaged into virions. In contrast, a phosphoablative mutant (S207A) remained cytosolic and maintained full aminoacylation activity but failed to rescue infectivity and was not packaged. These findings suggest that HIV-1 takes advantage of the dynamic nature of the MSC to redirect and coopt cellular translation factors to enhance viral replication. IMPORTANCE Human tRNALys3, the primer for reverse transcription, and LysRS are essential host factors packaged into HIV-1 virions. Previous studies found that tRNALys3 packaging depends on interactions between LysRS and HIV-1 Gag; however, many details regarding the mechanism of tRNALys3 and LysRS packaging remain unknown. LysRS is normally sequestered in a high-molecular-weight multi-aminoacyl-tRNA synthetase complex (MSC), restricting the pool of free LysRS-tRNALys. Mounting evidence suggests that LysRS is released under a variety of stimuli to perform alternative functions within the cell. Here, we show that HIV-1 infection results in a free pool of LysRS that is relocalized to the nucleus of target cells. Blocking this pathway in HIV-1-producing cells resulted in less infectious progeny virions. Understanding the mechanism by which LysRS is recruited into the viral assembly pathway can be exploited for the development of specific and effective therapeutics targeting this nontranslational function.

scholarly journals The Effect of Geometrical Isomerism of 3,5-Dicaffeoylquinic Acid on Its Binding Affinity to HIV-Integrase Enzyme: A Molecular Docking Study

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Mpho M. Makola ◽  
Ian A. Dubery ◽  
Gerrit Koorsen ◽  
Paul A. Steenkamp ◽  
Mwadham M. Kabanda ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Density Functional ◽  
Catalytic Domain ◽  
Synergistic Activity ◽  
Hiv Integrase ◽  
Molecular Docking Study ◽  
Geometrical Isomers ◽  
Catalytic Core ◽  
Dicaffeoylquinic Acid ◽  
Hiv 1

A potent plant-derived HIV-1 inhibitor, 3,5-dicaffeoylquinic acid (diCQA), has been shown to undergo isomerisation upon UV exposure where the naturally occurring3trans,5trans-diCQA isomer gives rise to the3cis,5trans-diCQA,3trans,5cis-diCQA, and3cis,5cis-diCQA isomers. In this study, inhibition of HIV-1 INT by UV-induced isomers was investigated using molecular docking methods. Here, density functional theory (DFT) models were used for geometry optimization of the 3,5-diCQA isomers. The YASARA and Autodock VINA software packages were then used to determine the binding interactions between the HIV-1 INT catalytic domain and the 3,5-diCQA isomers and the Discovery Studio suite was used to visualise the interactions between the isomers and the protein. The geometrical isomers of 3,5-diCQA were all found to bind to the catalytic core domain of the INT enzyme. Moreover, thecisgeometrical isomers were found to interact with the metal cofactor of HIV-1INT, a phenomenon which has been linked to antiviral potency. Furthermore, the3trans,5cis-diCQA isomer was also found to interact with both LYS156 and LYS159 which are important residues for viral DNA integration. The differences in binding modes of these naturally coexisting isomers may allow wider synergistic activity which may be beneficial in comparison to the activities of each individual isomer.

scholarly journals Cellular Distribution of Lysyl-tRNA Synthetase and Its Interaction with Gag during Human Immunodeficiency Virus Type 1 Assembly

2004 ◽  
Vol 78 (14) ◽  
pp. 7553-7564 ◽  
Author(s):  
Rabih Halwani ◽  
Shan Cen ◽  
Hassan Javanbakht ◽  
Jenan Saadatmand ◽  
Sunghoon Kim ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Primary Source ◽  
Free Cell ◽  
Trna Synthetase ◽  
Complex Iii ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Lysyl-tRNA synthetase (LysRS) is packaged into human immunodeficiency virus type 1 (HIV-1) via its interaction with Gag, and this enzyme facilitates the selective packaging of tRNA3 Lys, the primer for initiating reverse transcription, into HIV-1. The Gag/LysRS interaction is detected at detergent-resistant membrane but not in membrane-free cell compartments that contain Gag and LysRS. LysRS is found (i) in the nucleus, (ii) in a cytoplasmic high-molecular-weight aminoacyl-tRNA synthetase complex (HMW aaRS complex), (iii) in mitochondria, and (iv) associated with plasma membrane. The cytoplasmic form of LysRS lacking the mitochondrial import signal was previously shown to be efficiently packaged into virions, and in this report we also show that LysRS compartments in nuclei, in the HMW aaRS complex, and at the membrane are also not required as a primary source for viral LysRS. Exogenous mutant LysRS species unable to either enter the nucleus or bind to the cell membrane are still incorporated into virions. Many HMW aaRS components are not packaged into the virion along with LysRS, and the interaction of LysRS with p38, a protein that binds tightly to LysRS in the HMW aaRS complex, is not required for the incorporation of LysRS into virions. These data indicate that newly synthesized LysRS may interact rapidly with Gag before the enzyme has the opportunity to move to the above-mentioned cellular compartments. In confirmation of this idea, we found that newly synthesized LysRS is associated with Gag after a 10-min pulse with [35S]cysteine/methionine. This observation is also supported by previous work indicating that the incorporation of LysRS into HIV-1 is very sensitive to the inhibition of new synthesis of LysRS.

Brownian and Essential Dynamics Studies of the HIV-1 Integrase Catalytic Domain

1998 ◽  
Vol 16 (3) ◽  
pp. 733-745 ◽  
Author(s):  
Wolfgang Weber ◽  
Hagop Demirdjian ◽  
Roberto D. Lins ◽  
James M. Briggs ◽  
Ricardo Ferreira ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Essential Dynamics ◽  
Hiv 1

Escherichia coli LysU is a potential surrogate for human lysyl tRNA synthetase in interactions with the C-terminal domain of HIV-1 capsid protein

2013 ◽  
Vol 11 (4) ◽  
pp. 612-620 ◽  
Author(s):  
Nonlawat Boonyalai ◽  
James R. Pullen ◽  
Mohd Firdaus Abdul Wahab ◽  
Michael Wright ◽  
Andrew D. Miller
Keyword(s):  
Escherichia Coli ◽  
Capsid Protein ◽  
Trna Synthetase ◽  
Terminal Domain ◽  
Hiv 1

Prediction of HIV-1 Integrase/Viral DNA Interactions in the Catalytic Domain by Fast Molecular Docking

2004 ◽  
Vol 47 (4) ◽  
pp. 821-828 ◽  
Author(s):  
Adeyemi A. Adesokan ◽  
Victoria A. Roberts ◽  
Keun Woo Lee ◽  
Roberto D. Lins ◽  
James M. Briggs
Keyword(s):  
Molecular Docking ◽  
Catalytic Domain ◽  
Dna Interactions ◽  
Viral Dna ◽  
Hiv 1

scholarly journals Critical Role of Helix 4 of HIV-1 Capsid C-terminal Domain in Interactions with Human Lysyl-tRNA Synthetase

2007 ◽  
Vol 282 (44) ◽  
pp. 32274-32279 ◽  
Author(s):  
Brandie J. Kovaleski ◽  
Robert Kennedy ◽  
Ahmad Khorchid ◽  
Lawrence Kleiman ◽  
Hiroshi Matsuo ◽  
...  
Keyword(s):  
Critical Role ◽  
Trna Synthetase ◽  
Terminal Domain ◽  
Hiv 1
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