Structure of HIV-1 reverse transcriptase with the inhibitor beta-Thujaplicinol bound at the RNase H active site.

Autor: Himmel DM; Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA., Maegley KA; Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA., Pauly TA; Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA., Bauman JD; Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA., Das K; Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA., Dharia C; Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA., Clark AD Jr; Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA., Ryan K; Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA., Hickey MJ; Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA., Love RA; Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA., Hughes SH; HIV Drug Resistance Program, NCI-Frederick, Frederick, MD 21702-1201, USA., Bergqvist S; Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA., Arnold E; Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA. Electronic address: arnold@cabm.rutgers.edu.
Jazyk: angličtina
Zdroj: Structure (London, England : 1993) [Structure] 2009 Dec 09; Vol. 17 (12), pp. 1625-1635.
DOI: 10.1016/j.str.2009.09.016
Abstrakt: 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, beta-thujaplicinol, bound at the RNH active site of both HIV-1 RT and an isolated RNH domain. beta-thujaplicinol chelates two divalent metal ions at the RNH active site. We provide biochemical evidence that beta-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: MEDLINE
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