3IG1

HIV-1 Reverse Transcriptase with the Inhibitor beta-Thujaplicinol Bound at the RNase H Active Site

Summary for 3IG1

• Entry DOI: 10.2210/pdb3ig1/pdb
• Descriptor: HIV-1 Reverse Transcriptase p66 subunit, HIV-1 Reverse Transcriptase p51 subunit, 2,7-dihydroxy-4-(propan-2-yl)cyclohepta-2,4,6-trien-1-one, ... (5 entities in total)
• Functional Keywords: rnase h inhibitor, protein-inhibitor complex, structure-based drug design, tropolones, tropylium ion, divalent cation chelator, aids, dna-directed dna polymerase, metal-binding, multifunctional enzyme, nucleotidyltransferase, rna-binding, rna-directed dna polymerase, transferase
• Biological source: Human immunodeficiency virus type 1 BH10 (HIV-1); More
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03366 P03366
• Total number of polymer chains: 2
• Total formula weight: 114144.58

Authors

Himmel, D.M.,Maegley, K.A.,Pauly, T.A.,Arnold, E. (deposition date: 2009-07-27, release date: 2010-01-26, Last modification date: 2023-09-06)

Primary citation

Himmel, D.M.,Maegley, K.A.,Pauly, T.A.,Bauman, J.D.,Das, K.,Dharia, C.,Clark, A.D.,Ryan, K.,Hickey, M.J.,Love, R.A.,Hughes, S.H.,Bergqvist, S.,Arnold, E.
Structure of HIV-1 reverse transcriptase with the inhibitor beta-Thujaplicinol bound at the RNase H active site.
Structure, 17:1625-1635, 2009

PubMed 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.

PubMed: 20004166
DOI: 10.1016/j.str.2009.09.016

Experimental method

X-RAY DIFFRACTION (2.8 Å)