Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α-APA R 95845 at 2.8 å resolution
| Autor: | P. A. J. Janssen, Christopher J. Michejda, S.H. Hughes, Y. Hsiou, Eddy Arnold, Arthur D. Clark, S Jessen, Jianping Ding, Kalyan Das, Rudi Pauwels, Xiaode Lu, Wanyi Zhang, Richard H. Smith, Chris Tantillo, Luc Koymans, Henri Moereels, Koenraad Jozef Lodewijk Marcel Andries, Alfredo Jacobo-Molina, M.Kroeger Koepke |
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| Rok vydání: | 1995 |
| Předmět: |
Models
Molecular Organomercury Compounds Protein Conformation protein-drug interactions HIV Antibodies Crystallography X-Ray 01 natural sciences chemistry.chemical_compound Structural Biology Acetamides Aromatic amino acids Polymerase chemistry.chemical_classification 0303 health sciences Fourier Analysis biology Drug Resistance Microbial RNA-Directed DNA Polymerase Methylmercury Compounds HIV Reverse Transcriptase 3. Good health AIDS Reverse Transcriptase Inhibitors Protein Binding Stereochemistry Protein subunit Molecular Sequence Data polymerase structure 010402 general chemistry Antiviral Agents Immunoglobulin Fab Fragments 03 medical and health sciences mechanism of non-nucleoside Amino Acid Sequence Molecular Biology 030304 developmental biology drug resistance Binding Sites Sequence Homology Amino Acid Acetophenones Active site RNA Molecular biology Reverse transcriptase 0104 chemical sciences Enzyme chemistry biology.protein Deoxyuracil Nucleotides Sequence Alignment DNA |
| Zdroj: | Structure. 3:365-379 |
| ISSN: | 0969-2126 |
| Popis: | 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 α -anilinophenylacetamide ( α -APA) R 95845 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 α -APA. The overall fold of HIV-1 RT in complex with α -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. Conclusion 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 α -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. |
| Databáze: | OpenAIRE |
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