3K2P

HIV-1 Reverse Transcriptase Isolated RnaseH Domain with the Inhibitor beta-thujaplicinol Bound at the Active Site

Summary for 3K2P

• Entry DOI: 10.2210/pdb3k2p/pdb
• Descriptor: Reverse Transcriptase, MANGANESE (II) ION, 2,7-dihydroxy-4-(propan-2-yl)cyclohepta-2,4,6-trien-1-one, ... (4 entities in total)
• Functional Keywords: rnase h inhibitor, reverse transcriptase, aids, hiv, protein-inhibitor complex, structure-based drug design, tropolones, tropylium ion, divalent cation chelator, metal-binding, rna-binding, hydrolase
• Biological source: Human immunodeficiency virus type 1 (HIV-1)
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03366
• Total number of polymer chains: 2
• Total formula weight: 30490.22

Authors

Pauly, T.A.,Himmel, D.M.,Maegley, K.,Arnold, E. (deposition date: 2009-09-30, release date: 2010-02-09, Last modification date: 2024-02-21)

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 (2.04 Å)