HIV-1 Reverse Transcriptase in Complex with Nevirapine: Difference between revisions

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== Introduction ==
== Introduction ==
<scene name='HIV-1_Reverse_Transcriptase_in_Complex_with_Nevirapine/First_edit/1'>Reverse Transcriptase</scene> is a viral encoded enzyme that converts the viral single-stranded RNA genome into a double-stranded DNA provirus that is integrated into the host chromosome in the host cell's nucleus. The process of converting viral ssRNA into dsDNA that can incorporate into the host chromosome is called retrotranscription, and is characteristic of all retrovirus. HIV-1 reverse transcriptase is encoded by the human immunodeficiency virus, well known as the etiological agent of acquired immunodeficiency syndrome (AIDS).  
<scene name='HIV-1_Reverse_Transcriptase_in_Complex_with_Nevirapine/Nevirapine_ternary_complex/1'>Reverse Transcriptase</scene> is a viral encoded enzyme that converts the viral single-stranded RNA genome into a double-stranded DNA provirus that is integrated into the host chromosome in the host cell's nucleus. The process of converting viral ssRNA into dsDNA that can incorporate into the host chromosome is called retrotranscription, and is characteristic of all retrovirus. HIV-1 reverse transcriptase is encoded by the human immunodeficiency virus, well known as the etiological agent of acquired immunodeficiency syndrome (AIDS).  


RT performs three catalytic steps: 1) RNA-dependent DNA polymerization to create a negative sense DNA strand that complements the positive sense viral RNA genome, 2) ribonuclease H cleavage of RNA in the RNA:DNA heteroduplex, and 3) DNA-dependent DNA polymerization to make a dsDNA using the previously synthesized negative sense DNA strand as a template. The dsDNA is transported to the nucleus where it integrates into the host cell's chromosome. HIV-1 is chronic and requires lifelong treatment with a combination of at least three different antiviral drugs. In addition, the emergence of drug-resistant HIV-1 strains means drugs with new viral targets are constantly being developed.   
RT performs three catalytic steps: 1) RNA-dependent DNA polymerization to create a negative sense DNA strand that complements the positive sense viral RNA genome, 2) ribonuclease H cleavage of RNA in the RNA:DNA heteroduplex, and 3) DNA-dependent DNA polymerization to make a dsDNA using the previously synthesized negative sense DNA strand as a template. The dsDNA is transported to the nucleus where it integrates into the host cell's chromosome. HIV-1 is chronic and requires lifelong treatment with a combination of at least three different antiviral drugs. In addition, the emergence of drug-resistant HIV-1 strains means drugs with new viral targets are constantly being developed.   
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RT is an asymmetric heterodimer composed of a 560 amino acid 66kDa subunit (p66) and a 440 amino acid 51kDa subunit (p51). The p66 and p55 domains are derived from cleavage of the same polyprotein precursor. The p51 is made from the C-terminal cleavage of the p66 subunit by HIV-1 protease. As a result, they share a common amino terminus, but the p51 subunit does not have an RNase H domain.  
RT is an asymmetric heterodimer composed of a 560 amino acid 66kDa subunit (p66) and a 440 amino acid 51kDa subunit (p51). The p66 and p55 domains are derived from cleavage of the same polyprotein precursor. The p51 is made from the C-terminal cleavage of the p66 subunit by HIV-1 protease. As a result, they share a common amino terminus, but the p51 subunit does not have an RNase H domain.  


The p66 subunit (color) contains two enzymatically active domains, polymerase (color)and RNase H (color). This polymerase is responsible for catalyzing the polymerization of DNA using either RNA or DNA as the template. The endonucleolytic ribonuclease H (RNase H) specifically degrades the RNA strand of RNA:DNA duplexes that are produced during retrotranscription. RT has a right-hand structure.<ref>PMID:10364165<ref/> The polymerase domain can be divided into several subdomains: the fingers (residues 1-85 and 118-155), palm (residues 86-117 and 156-236), thumb (237-318) and connecting (319-426). The RNase H domain consists of the C-terminal residues 427-560.
The p66 subunit contains two enzymatically active domains, polymerase (color)and RNase H (color). This polymerase is responsible for catalyzing the polymerization of DNA using either RNA or DNA as the template. The endonucleolytic ribonuclease H (RNase H) specifically degrades the RNA strand of RNA:DNA duplexes that are produced during retrotranscription. RT has a right-hand structure.<ref>PMID:10364165<ref/> The polymerase domain can be divided into several subdomains: the fingers (residues 1-85 and 118-155), palm (residues 86-117 and 156-236), thumb (237-318) and connecting (319-426). The RNase H domain consists of the C-terminal residues 427-560.


The p51 subunit (color) contains the same four subdomains as the polymerase domain in p66, but in different positions. The p51 subunit is therefore non-enzymatic, and instead stabilizes the proper folding of the catalytic p66 subunit. Instead of adopting an "open" catalytically-active conformation that can accommodate a nucleic acid template strand like p66, the p51 subunit is in a "closed" conformation and plays a largely structural role.<ref>PMID:1377403</ref>
The p51 subunit contains the same four subdomains as the polymerase domain in p66, but in different positions. The p51 subunit is therefore non-enzymatic, and instead stabilizes the proper folding of the catalytic p66 subunit. Instead of adopting an "open" catalytically-active conformation that can accommodate a nucleic acid template strand like p66, the p51 subunit is in a "closed" conformation and plays a largely structural role.<ref>PMID:1377403</ref>


== NNRTIs: Anti-retroviral Drugs ==
== NNRTIs: Anti-retroviral Drugs ==
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