Format

Send to

Choose Destination
Structure. 2009 Dec 9;17(12):1625-1635. doi: 10.1016/j.str.2009.09.016.

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

Author information

1
Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA.
2
Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA.
3
HIV Drug Resistance Program, NCI-Frederick, Frederick, MD 21702-1201, USA.
4
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.

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 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.

PMID:
20004166
PMCID:
PMC3365588
DOI:
10.1016/j.str.2009.09.016
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center