HIV-1 Reverse Transcriptase in Complex with Nevirapine: Difference between revisions
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== Structure of RT domains == | == Structure of RT domains == | ||
[[image:RT Polymerase and RNase H domains.jpg|thumb|left|400px|'''RT Polymerase and RNase H domains. Reprinted from Esposito et al PMID:22778958''']] | [[image:RT Polymerase and RNase H domains.jpg|thumb|left|400px|'''RT Polymerase and RNase H domains. Reprinted from Esposito et al PMID:22778958''']] | ||
[[image:Subdomains of RT.jpg|thumb| | {{Clear}} | ||
[[image:Subdomains of RT.jpg|thumb|left|400px|'''The subdomains of RT. Reprinted from Sluis-Cremer et al PMID:15544453''']] | |||
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RT is an <scene name='HIV-1_Reverse_Transcriptase_in_Complex_with_Nevirapine/Nevirapine_ternary_complex/1'>asymmetric heterodimer</scene> 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 <scene name='HIV-1_Reverse_Transcriptase_in_Complex_with_Nevirapine/Nevirapine_ternary_complex/1'>asymmetric heterodimer</scene> 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. | ||
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[[image:Effect of NNRTI binding on DNA polymerization by RT.jpg|thumb|left|400px|'''Effect of NNRTI binding on DNA polymerization by RT. Reprinted by permission from Macmillan Publishers Ltd: Nature Structural & Molecular Biology, copyright 2012''']] | [[image:Effect of NNRTI binding on DNA polymerization by RT.jpg|thumb|left|400px|'''Effect of NNRTI binding on DNA polymerization by RT. Reprinted by permission from Macmillan Publishers Ltd: Nature Structural & Molecular Biology, copyright 2012''']] | ||
[[Image:Effects of nevirapine on pol active site conformation and dNTP binding.jpg|thumb| | {{Clear}} | ||
[[Image:Effects of nevirapine on pol active site conformation and dNTP binding.jpg|thumb|left|450px|'''Effects of nevirapine on pol active site conformation and dNTP binding. Reprinted by permission from Macmillan Publishers Ltd: Nature Structural & Molecular Biology, copyright 2012''']] | |||
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== The NNRTI Binding Pocket == | == The NNRTI Binding Pocket == | ||
Although nonnucleoside RT inhibitors are structurally diverse compounds, they all bind RT in the same location - <scene name='HIV-1_Reverse_Transcriptase_in_Complex_with_Nevirapine/Hydrophobic_binding_pocket/1'>the NNRTI hydrophobic binding pocket</scene>. The pocket is located in the palm domain of the p66 subunit between the β6-β10-β9 and β12-β13-β14 sheets approximately 10 angstroms from the three catalytic asp residues that make up the polymerase active site.<ref name= "kohlstaedt"/> The NNRTI BP is mostly hydrophobic in nature with considerable aromatic residues (Y181, Y188, F227, W229, and Y232), but also contains several hydrophilic residues (K101, K103, S105, D192, and E224 of the p66 subunit and E138 of the β7-β8 loop of the p51 subunit).<ref name="sluis"/> NNRTIs most likely access the binding pocket at the p66/p51 heterodimer interface surrounded by <scene name='HIV-1_Reverse_Transcriptase_in_Complex_with_Nevirapine/Nnrti_binding_pocket/2'>residues L100, K101, K103, V179, and Y181 of the p66 subunit and E138 of the p51 subunit</scene>.<ref name="hsiou">PMID:8805568 </ref> These residues are colored tan in the binding pocket scene. Actually, in the absence of ligand, the side chains of <scene name='HIV-1_Reverse_Transcriptase_in_Complex_with_Nevirapine/Y181_and_y188/2'>Y181 and Y188</scene> point into the core, so the binding pocket doesn't exist in the free enzyme. The binding of NNRTI to HIV RT causes these side chains to shift away and make room for the ligand to enter the binding pocket.<ref name="hsiou"/> | Although nonnucleoside RT inhibitors are structurally diverse compounds, they all bind RT in the same location - <scene name='HIV-1_Reverse_Transcriptase_in_Complex_with_Nevirapine/Hydrophobic_binding_pocket/1'>the NNRTI hydrophobic binding pocket</scene>. The pocket is located in the palm domain of the p66 subunit between the β6-β10-β9 and β12-β13-β14 sheets approximately 10 angstroms from the three catalytic asp residues that make up the polymerase active site.<ref name= "kohlstaedt"/> The NNRTI BP is mostly hydrophobic in nature with considerable aromatic residues (Y181, Y188, F227, W229, and Y232), but also contains several hydrophilic residues (K101, K103, S105, D192, and E224 of the p66 subunit and E138 of the β7-β8 loop of the p51 subunit).<ref name="sluis"/> NNRTIs most likely access the binding pocket at the p66/p51 heterodimer interface surrounded by <scene name='HIV-1_Reverse_Transcriptase_in_Complex_with_Nevirapine/Nnrti_binding_pocket/2'>residues L100, K101, K103, V179, and Y181 of the p66 subunit and E138 of the p51 subunit</scene>.<ref name="hsiou">PMID:8805568 </ref> These residues are colored tan in the binding pocket scene. Actually, in the absence of ligand, the side chains of <scene name='HIV-1_Reverse_Transcriptase_in_Complex_with_Nevirapine/Y181_and_y188/2'>Y181 and Y188</scene> point into the core, so the binding pocket doesn't exist in the free enzyme. The binding of NNRTI to HIV RT causes these side chains to shift away and make room for the ligand to enter the binding pocket.<ref name="hsiou"/> | ||
