1hni
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STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN A COMPLEX WITH THE NONNUCLEOSIDE INHIBITOR ALPHA-APA R 95845 AT 2.8 ANGSTROMS RESOLUTION
OverviewOverview
BACKGROUND: HIV-1 reverse transcriptase (RT) is a multifunctional enzyme, that copies the RNA genome of HIV-1 into DNA. It is a heterodimer composed, of a 66 kDa (p66) and a 51 kDa (p51) subunit. HIV-1 RT is a crucial target, for structure-based drug design, and potent inhibitors have been, identified, whose efficacy, however, is limited by drug resistance., RESULTS: The crystal structure of HIV-1 RT in complex with the, non-nucleoside inhibitor alpha-anilinophenyl-acetamide (alpha-APA) R95845, has been determined at 2.8 A resolution. The inhibitor binds in a, hydrophobic pocket near the polymerase active site. The pocket contains, five aromatic amino acid residues and the interactions of the side chains, of these residues with the aromatic rings of non-nucleoside inhibitors, appear to be important for inhibitor binding. Most of the amino acid, residues where mutations have been correlated with high levels of, resistance to non-nucleoside inhibitors of HIV-1 RT are located close to, alpha-APA. The overall fold of HIV-1 RT in complex with alpha-APA is, similar to that found when in complex with nevirapine, another, non-nucleoside inhibitor, but there are significant conformational changes, relative to an HIV-1 RT/DNA/Fab complex. CONCLUSIONS: The non-nucleoside, inhibitor-binding pocket has a flexible structure whose mobility may be, required for effective polymerization, and may be part of a hinge that, permits relative movements of two subdomains of the p66 subunit denoted, the 'palm' and 'thumb'. An understanding of the structure of the, inhibitor-binding pocket, of the interactions between HIV-1 RT and, alpha-APA, and of the locations of mutations that confer resistance to, inhibitors provides a basis for structure-based design of chemotherapeutic, agents for the treatment of AIDS.
About this StructureAbout this Structure
1HNI is a Protein complex structure of sequences from Human immunodeficiency virus 1 with AAA as ligand. Active as RNA-directed DNA polymerase, with EC number 2.7.7.49 Full crystallographic information is available from OCA.
ReferenceReference
Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor alpha-APA R 95845 at 2.8 A resolution., Ding J, Das K, Tantillo C, Zhang W, Clark AD Jr, Jessen S, Lu X, Hsiou Y, Jacobo-Molina A, Andries K, et al., Structure. 1995 Apr 15;3(4):365-79. PMID:7542140
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