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

doi:10.1016/j.str.2009.09.016

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

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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, …

Structure (London), Vol.17(12), pp.1625-1635

12/09/2009

DOI: https://doi.org/10.1016/j.str.2009.09.016

PMCID: PMC3365588

PMID: 20004166

Abstract

PROTEINS

MICROBIO

RNA

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.

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Title: Structure of HIV-1 Reverse Transcriptase with the Inhibitor β-Thujaplicinol Bound at the RNase H Active Site
Creators: Daniel M Himmel - Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA
Karen A Maegley - Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA
Tom A Pauly - Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA
Joseph D Bauman - Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA
Kalyan Das - Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA
Chhaya Dharia - Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA
Arthur D Clark - Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA
Kevin Ryan - Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA
Michael J Hickey - Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA
Robert A Love - Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA
Stephen H Hughes - HIV Drug Resistance Program, NCI-Frederick, Frederick, MD 21702-1201, USA
Simon Bergqvist - Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA
Eddy Arnold - Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8021, USA
Publication Details: Structure (London), Vol.17(12), pp.1625-1635
Date published: 12/09/2009
Publisher: Elsevier Ltd
Academic Unit: Center for Advanced Biotechnology and Medicine
Language: English
Resource Type: Journal article
Identifiers: 991031654832304646