HIV-1 Reverse Transcriptase in Complex with Nevirapine

Function of HIV Reverse Transcriptase

Reverse Transcriptase 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 carries out several activities related to retrotranscription: RNA and DNA-dependent DNA synthesis, RNase H activity, strand transfer, and strand displacement synthesis.

spinqualitylabelsall models Crystal Structure of HIV-1 Reverse Transcriptase with DNA and the nonnucleoside inhibitor nevirapine (PDB entry 3V81) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Polymerase active site residues Nevirapine as an Anti-retroviral Drug RT is a prime target for anti-HIV drugs because of its essential role in the viral life cycle. A wide variety of drugs have been developed to target this enzyme in order to decrease the infectivity of HIV and slow the progression of this chronic disease. One class of drugs, called non-nucleoside reverse transcriptase inhibitors (NNRTIs), contain compounds that bind noncompetitively to a hydrophobic pocket near the polymerase active site. NNRTIs are a group of small hydrophobic compounds with diverse structures that inhibit HIV-1 but not HIV-2 RT. Binding of these compounds inhibit polymerization of nucleic acid by distorting the protein. Nevirapine is a first generation NNRTI, which binds RT in a butterfly-like conformation. Several factors stabilize its interaction with RT's hydrophobic pocket, and the conformational changes it causes in RT essentially inhibits DNA synthesis. Unfortunately, single amino acid mutations in the binding pocket can significantly decrease the antiviral potency of this drug. Structure of RT domains 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). 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.

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