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evolution
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RNase H acts as gene modifier, driver of evolution and antiviral defense, overview
evolution
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the N-terminal amino acid residue of HIV-1 RNase H is highly conserved
malfunction
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antiviral activity of 2-hydroxy-4-methoxycarbonylisoquinoline-1,3(2H,4H)-dione is probably due to the RNase H inhibition
malfunction
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patients treated with nucleoside reverse transcriptase inhibitors develop classical patterns of resistance-associated mutations in the pol domain. Thymidine analogue mutations, TAMs, arise with zidovudine and stavudine treatment, which encompass M41L, D67N, K70R, L210W, T215F/Y, and K219Q/E/N. Different patterns of thymidine analogue mutations accumulate in patients, which segregate into two distinct pathways named TAM-1 and TAM-2. The TAM-1 pathway includes M41L, L210W and T215Y, whereas the TAM-2 pathway includes D67N, K70R, T215F and K219Q/E/N
malfunction
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PEGylation as a tool for engineering the M-MuLV RT derivative deficient in RNase H activity, overview
malfunction
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severe defects in RNase H activity alone, exemplified by the P236L mutant, appear sufficient to cause a substantial reduction in fitness. Reductions in reverse transcriptase content decrease both polymerization and RNase H activity in virions
malfunction
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RNase H-deficient HIV-1 reverse transcriptase shows altered error specificity during DNA-dependent DNA synthesis
malfunction
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an HIV-1 mutant can tolerate an about 10fold higher RNase H activity
malfunction
effect of N-terminal deletion on monomer-dimer interconversion kinetics, overview
malfunction
Human immunodeficiency virus type 1 subtype C
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identification of nucleoside reverse transcriptase inhibitor (NRTI) treatment-related mutations in RNase H of HIV-1 subtype C, overview
malfunction
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RNase H N-terminal mutations impact intravirion protein levels and viral infectivity. Reverse transcriptase (RT) with an RNaseHN-terminal mutation is still degraded in the absence of active viral protease
malfunction
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the Q294P mutant of HIV-2 RT has about 10fold higher RNase H activity than the wild-type. Infectious HIV-2 cannot bear the replacement of the RT's Gln294 by the HIV-1 RT Pro counterpart, as it results in substantially reduced HIV-2 replication and fast reversions to the wild-type Gln294 virus. Critical role of maintaining low RT-associated RNase H activity in HIV-2
malfunction
Human immunodeficiency virus type 1 group O subtype B
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the substitution of Pro for Leu-92 renders an HIV-1 reverse transcriptase without strand transfer activity but retaining wild-type DNA polymerase and RNase H activities. Introduction of L92P produces a 3-4fold increase in the dissociation equilibrium constant (Kd) for DNA/DNA template-primers, suggesting that the strand transfer defect is a consequence of impaired nucleic acid binding
malfunction
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two mutations in HIV-1 RNase H, Y501R and Y501W, result in a reduction of inhibitor potency, thus indicating their potential role in providing resistance to the inhibitor
malfunction
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patients treated with nucleoside reverse transcriptase inhibitors develop classical patterns of resistance-associated mutations in the pol domain. Thymidine analogue mutations, TAMs, arise with zidovudine and stavudine treatment, which encompass M41L, D67N, K70R, L210W, T215F/Y, and K219Q/E/N. Different patterns of thymidine analogue mutations accumulate in patients, which segregate into two distinct pathways named TAM-1 and TAM-2. The TAM-1 pathway includes M41L, L210W and T215Y, whereas the TAM-2 pathway includes D67N, K70R, T215F and K219Q/E/N
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malfunction
Human immunodeficiency virus type 1 group O subtype B ESP49
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the substitution of Pro for Leu-92 renders an HIV-1 reverse transcriptase without strand transfer activity but retaining wild-type DNA polymerase and RNase H activities. Introduction of L92P produces a 3-4fold increase in the dissociation equilibrium constant (Kd) for DNA/DNA template-primers, suggesting that the strand transfer defect is a consequence of impaired nucleic acid binding
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physiological function
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increasing the stoichiometry of RNase H relative to the amount of functional DNA polymerase by virions engineered to contain phenotypic mixtures of wild-type and RNase H catalytic site point mutant D524N reverse transcriptase, has minimal effects on direct repeat deletion frequency. DNA synthesis is error prone when directed principally by RNase H mutant reverse transcriptase, suggesting a role for RNase H catalytic integrity in the fidelity of intracellular reverse transcription
physiological function
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the process of reverse transcription involves the copying of the single-stranded RNA of the viral genome into double-stranded DNA. This requires that reverse transcriptase is able to act at times as a RNA-dependent DNA polymerase, a DNA-dependent DNA polymerase, and as an RNase H that cleaves the RNA of RNA/DNA hybrids. These activities are coordinated temporally and spatially. As all three of these processes are absolutely required for the successful completion of reverse transcription, role of RNase H in (+)-strand priming and in strand transfer and (-)-strand primer removal, overview
physiological function
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the process of reverse transcription involves the copying of the single-stranded RNA of the viral genome into double-stranded DNA. This requires that reverse transcriptase is able to act at times as a RNA-dependent DNA polymerase, a DNA-dependent DNA polymerase, and as an RNase H that cleaves the RNA of RNA/DNA hybrids. These activities are coordinated temporally and spatially. As all three of these processes are absolutely required for the successful completion of reverse transcription, role of RNase H in (+)-strand priming and in strand transfer and (-)-strand primer removal, overview
physiological function
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the retroviral RNase H degrades the RNA template following first strand synthesis, generates primers for second strand synthesis, and eliminates the t-RNA primer
physiological function
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the reverse transcriptase generates an RNA/DNA hybrid that is a substrate for RNase H. The RNA/DNA hybrid is degraded to generate a nascent minus-strand single-stranded DNA. As DNA synthesis proceeds, RNase H degrades the RNA strand
physiological function
the enzyme activity and substrate specificity is controlled by the RNase H primer grip, and the width of the minor groove and the trajectroy of the RNA:DNA, both in a sequence-dependent manner
physiological function
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RNase H activity is essential for virus infectivity
physiological function
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HIV reverse transcriptase plays a central role in viral replication and requires coordination of both polymerase and RNaseH activities. HIV-1 reverse transcriptase polymerase and RNase H (ribonuclease H) active sites work simultaneously and independently
physiological function
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HIV-1 reverse trancriptase (RT) is a key multifunctional enzyme which combines an RNA-dependent DNA polymerase activity (RDDP) and a ribonuclease H (RNase H) function, both essential for the viral genome replication
physiological function
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low ribonuclease H (RNase H) activity of HIV-2 reverse transcriptase (RT) relative to HIV-1 RT. Residue Gln294 in HIV-2 RT accounts for this RNase H reduction (the comparable residue in HIV-1 RT is Pro294), as the Q294P mutant of HIV-2 RT has about 10fold higher RNase H activity
physiological function
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replication of human immunodeficiency virus 1 (HIV-1) involves conversion of its single-stranded RNA genome to double-stranded DNA, which is integrated into the genome of the host. This conversion is catalyzed by reverse transcriptase (RT), which possesses DNA polymerase and RNase H domains. When the RNA/DNA hybrid is immobilized at the polymerase active site, RNase H cleavage occurs, experimentally verifying that the substrate can simultaneously interact with both active sites
physiological function
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reverse transcriptase (RT) acts in concert with the RNase H catalyzing retroviral replication, the retroviral ribonuclease H (RNase H) in retrovirus particles is essential component for the replication of viral RNA via an RNA/DNA hybrid intermediate to double-stranded DNA. RNase H is a part of the reverse transcriptase (RT) in retroviruses. But the enzyme has its proper role, impact on evolution and importance for the degradation of nucleic acids in various biological processes
physiological function
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ribonuclease H (RNase H) is an enzyme that cleaves RNA strand of RNA/DNA hybrid to produce 5'-phosphate and 3'-hydroxyl termini with a two-metal-ion catalysis mechanism. HIV-1 reverse transcriptase (RT) is a heterodimer consisting of a P66 subunit and a P51 subunit. The P66 subunit contains a C-terminal RNase H domain, which exhibits RNase H activity either in the presence of Mg2+ or Mn2+ ions
physiological function
Human immunodeficiency virus type 1 group M subtype B
template-primer binding affinity and RNase H cleavage specificity contribute to the strand transfer efficiency of HIV-1 reverse transcriptase
physiological function
Human immunodeficiency virus type 1 group O subtype B
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template-primer binding affinity and RNase H cleavage specificity contribute to the strand transfer efficiency of HIV-1 reverse transcriptase
physiological function
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the nature of the N-terminal amino acid residue of HIV-1 RNase H is critical for the stability of reverse transcriptase (RT) in viral particles. Degradation of reverse transcriptase (RT) in RNase H N-terminal mutants occurs in the absence of active viral protease in the virion. Importance of the RNase H N-terminal residue in the dimerization of RT subunits. RNase H is an HIV-1 protein that has the potential to be a substrate for the N-end rule pathway, which is an ubiquitin-dependent proteolytic system in which the identity of the N-terminal amino acid determines the half-life of a protein. HIV-1 proteins are initially made as part of a polyprotein that is cleaved by the viral protease into the proteins that form the virus particle, RT is subject to an internal cleavage event leading to the formation of two subunits in the virion: a p66 subunit and a p51 subunit that lacks the RNase H domain. Importance of the N-terminal amino acid residue of RNase H in the early life cycle of HIV-1
physiological function
Human immunodeficiency virus type 1 group O subtype B ESP49
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template-primer binding affinity and RNase H cleavage specificity contribute to the strand transfer efficiency of HIV-1 reverse transcriptase
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physiological function
Human immunodeficiency virus type 1 group M subtype B BH10
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template-primer binding affinity and RNase H cleavage specificity contribute to the strand transfer efficiency of HIV-1 reverse transcriptase
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additional information
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catalytically important residues of the RNase H activity are Asp524 and Asp583
additional information
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HIV-1 reverse transcriptase has two associated activities, DNA polymerase and RNase H, both essential for viral replication and validated drug targets
additional information
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Q294 is highly conserved in HIV-2 isolates
additional information
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role of RNase H activity in drug resistance, the RNase H domains can affect the susceptibility of RT to non-nucleoside reverse transcriptase inhibitors and nucleos(t)ide reverse transcriptase inhibitors. Furthermore, RNase H activity itself is implicated in the mechanism of resistance to nucleoside reverse transcriptase inhibitors such as 3'-azidodeoxythymidine, and also to non-nucleoside reverse transcriptase inhibitors such as nevirapine. RNase H exists as a domain in the larger enzyme HIV-1 reverse transcriptase, structure and function of HIV-1 RNase H, overview
additional information
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RT is a unique viral protein containing two enzymatic properties, i.e. RNase H cleavage activity and RNA- and DNA-dependent DNA polymerase activity
additional information
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the active site of RNase H consists of four highly conserved carboxylate residues, D443, E478, D498, and D549, and requires Mg2+ or Mn2+ for its catalytic activity
additional information
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the RNase H activity, which degrades RNA from RNA/DNA hybrids endonucleolytically, is part of the HIV reverse transcriptase
additional information
the polypurine tract, PPT, a purine-rich segment from the HIV-1 genome, is resistant to RNase H cleavage and is used as a primer for second DNA strand synthesis. PPT-enzyme complex structure, detailed overview
additional information
Human immunodeficiency virus type 1 group M subtype B
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enzyme domain RNH structure-function relationship analysis, overview
additional information
Human immunodeficiency virus type 1 group M subtype B
for enzyme-inhibitor structural modelling, coordinates of the following retroviral RT-RT inhibitor structures are used: HIV RT-MK1 (PDB ID 3LP0) and HIV RT-MK2 (PDB ID 3LP1)
additional information
homology model of substrate- and inhibitor-bound HIV-1 RNase H, molecular docking, overview
additional information
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homology model of substrate- and inhibitor-bound HIV-1 RNase H, molecular docking, overview
additional information
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molecular dynamics simulations and determination of the conformation of the complex in which the unwound RNA/DNA substrate simultaneously interacts with the polymerase and RNase H active sites. Existence of a transient conformation of the HIV-1 by reverse transcriptase (RT) substrate complex, which is important for modulating and coordinating the enzymatic activities of HIV-1 RT
additional information
Human immunodeficiency virus type 1 group M subtype B
nucleotide analogues can enhance strand transfer by slowing DNA polymerization kinetics. Contribution of dissociation rate constants (koff) to the strand transfer efficiency of HIV-1 RTs, overview
additional information
Human immunodeficiency virus type 1 group O subtype B
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nucleotide analogues can enhance strand transfer by slowing DNA polymerization kinetics. Contribution of dissociation rate constants (koff) to the strand transfer efficiency of HIV-1 RTs, overview
additional information
predictions of sequence tolerance suggest that phenylalanine and tyrosine are structurally preferred at residues 440 and 441, respectively, which are the P1 and P1' substrate residues known to require bulky side chains for substrate specificity. The processing site residues, which are critical for protease substrate specificity and must be exposed to the solvent for efficient processing, also function to maintain proper RNH folding in the p66/p51 heterodimer. Molecular dynamics simulations of wild-type and mutant RNH enzyme domains
additional information
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the isolated RNase H domain of HIV-1 RT (RNHHIV) is inactive, possibly due to the lack of a substrate binding ability, disorder of a loop containing His539, and increased flexibility. The N-terminal substrate binding domain, termed hybrid binding domain (TmaHBD), from Thermotoga maritima RNase H1 and the N-terminal domain (BstNTD) from Bacillus stearothermophilus RNase H2 both function as an RNA/DNA hybrid binding tag, and greatly increase the substrate binding affinity and Mn2+-dependent activity of RNHHIV but do not restore the Mg2+-dependent activity of RNHHIV
additional information
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RT is a unique viral protein containing two enzymatic properties, i.e. RNase H cleavage activity and RNA- and DNA-dependent DNA polymerase activity
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additional information
Human immunodeficiency virus type 1 group O subtype B ESP49
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nucleotide analogues can enhance strand transfer by slowing DNA polymerization kinetics. Contribution of dissociation rate constants (koff) to the strand transfer efficiency of HIV-1 RTs, overview
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additional information
Human immunodeficiency virus type 1 group M subtype B BH10
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enzyme domain RNH structure-function relationship analysis, overview
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additional information
Human immunodeficiency virus type 1 group M subtype B BH10
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nucleotide analogues can enhance strand transfer by slowing DNA polymerization kinetics. Contribution of dissociation rate constants (koff) to the strand transfer efficiency of HIV-1 RTs, overview
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additional information
Human immunodeficiency virus type 1 group M subtype B BH10
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for enzyme-inhibitor structural modelling, coordinates of the following retroviral RT-RT inhibitor structures are used: HIV RT-MK1 (PDB ID 3LP0) and HIV RT-MK2 (PDB ID 3LP1)
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additional information
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homology model of substrate- and inhibitor-bound HIV-1 RNase H, molecular docking, overview
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