Structure of HIV-1 Reverse Transcriptase with the Inhibitor β-Thujaplicinol Bound at the RNase H Active Site

Daniel M. Himmel, Karen A. Maegley, Tom A. Pauly, Joseph D. Bauman, Kalyan Das, Chhaya Dharia, Arthur D. Clark, Kevin Ryan, Michael J. Hickey, Robert A. Love, Stephen H. Hughes, Simon Bergqvist, Eddy Arnold

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

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 Å and 2.04 Å 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.

Original languageEnglish (US)
Pages (from-to)1625-1635
Number of pages11
JournalStructure
Volume17
Issue number12
DOIs
StatePublished - Dec 9 2009

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

Keywords

  • MICROBIO
  • PROTEINS
  • RNA

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