Structure of HIV-1 reverse transcriptase with the inhibitor beta-Thujaplicinol bound at the RNase H active site
Autor: | Michael J. Hickey, Robert A. Love, Chhaya Dharia, Stephen H. Hughes, Karen A. Maegley, Daniel M. Himmel, Kevin Ryan, Arthur D. Clark, Simon Bergqvist, Eddy Arnold, Kalyan Das, Joseph D. Bauman, T.A. Pauly |
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Rok vydání: | 2009 |
Předmět: |
Models
Molecular MICROBIO PROTEINS DNA polymerase Protein Conformation Crystallography X-Ray Tropolone Article chemistry.chemical_compound Ribonucleases Structural Biology Catalytic Domain RNase H Molecular Biology Polymerase chemistry.chemical_classification biology Active site RNA Reverse transcriptase HIV Reverse Transcriptase Enzyme chemistry Biochemistry biology.protein Reverse Transcriptase Inhibitors DNA Protein Binding |
Zdroj: | Structure (London, England : 1993). 17(12) |
ISSN: | 1878-4186 |
Popis: | Summary Novel inhibitors are needed to counteract the rapid emergence of drug-resistant HIV variants. HIV-1 reverse transcriptase (RT) has both DNA polymerase and RNase H (RNH) enzymatic activities, but approved drugs that inhibit RT target the polymerase. Inhibitors that act against new targets, such as RNH, should be effective against all of the current drug-resistant variants. Here, we present 2.80 A and 2.04 A resolution crystal structures of an RNH inhibitor, β-thujaplicinol, bound at the RNH active site of both HIV-1 RT and an isolated RNH domain. β-thujaplicinol chelates two divalent metal ions at the RNH active site. We provide biochemical evidence that β-thujaplicinol is a slow-binding RNH inhibitor with noncompetitive kinetics and suggest that it forms a tropylium ion that interacts favorably with RT and the RNA:DNA substrate. |
Databáze: | OpenAIRE |
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