3LP2

HIV-1 reverse transcriptase with inhibitor

Summary for 3LP2

• Entry DOI: 10.2210/pdb3lp2/pdb
• Related: 3LP0 3LP1 3LP3
• Descriptor: Reverse transcriptase/ribonuclease H, p51 RT, 3-[4-(diethylamino)phenoxy]-6-(ethoxycarbonyl)-5,8-dihydroxy-7-oxo-7,8-dihydro-1,8-naphthyridin-1-ium, ... (5 entities in total)
• Functional Keywords: reverse transcriptase, rnase h, hiv, aids, aspartyl protease, capsid maturation, dna integration, dna-directed dna polymerase, endonuclease, host cytoplasm, host nucleus, host-virus interaction, hydrolase, magnesium, membrane, metal-binding, multifunctional enzyme, nuclease, nucleotidyltransferase, protease, rna-binding, rna-directed dna polymerase, transferase, viral nucleoprotein, virion, transferase-hydrolase complex, transferase/hydrolase
• Biological source: Human immunodeficiency virus type 1 (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 : P04585 P04585
• Total number of polymer chains: 2
• Total formula weight: 117119.88

Authors

Yan, Y.,Munshi, S.K.,Prasad, G.S.,Su, H.P. (deposition date: 2010-02-04, release date: 2010-06-09, Last modification date: 2024-02-21)

Primary citation

Su, H.P.,Yan, Y.,Prasad, G.S.,Smith, R.F.,Daniels, C.L.,Abeywickrema, P.D.,Reid, J.C.,Loughran, H.M.,Kornienko, M.,Sharma, S.,Grobler, J.A.,Xu, B.,Sardana, V.,Allison, T.J.,Williams, P.D.,Darke, P.L.,Hazuda, D.J.,Munshi, S.
Structural basis for the inhibition of RNase H activity of HIV-1 reverse transcriptase by RNase H active site-directed inhibitors.
J.Virol., 84:7625-7633, 2010

PubMed Abstract: HIV/AIDS continues to be a menace to public health. Several drugs currently on the market have successfully improved the ability to manage the viral burden in infected patients. However, new drugs are needed to combat the rapid emergence of mutated forms of the virus that are resistant to existing therapies. Currently, approved drugs target three of the four major enzyme activities encoded by the virus that are critical to the HIV life cycle. Although a number of inhibitors of HIV RNase H activity have been reported, few inhibit by directly engaging the RNase H active site. Here, we describe structures of naphthyridinone-containing inhibitors bound to the RNase H active site. This class of compounds binds to the active site via two metal ions that are coordinated by catalytic site residues, D443, E478, D498, and D549. The directionality of the naphthyridinone pharmacophore is restricted by the ordering of D549 and H539 in the RNase H domain. In addition, one of the naphthyridinone-based compounds was found to bind at a second site close to the polymerase active site and non-nucleoside/nucleotide inhibitor sites in a metal-independent manner. Further characterization, using fluorescence-based thermal denaturation and a crystal structure of the isolated RNase H domain reveals that this compound can also bind the RNase H site and retains the metal-dependent binding mode of this class of molecules. These structures provide a means for structurally guided design of novel RNase H inhibitors.

PubMed: 20484498
DOI: 10.1128/JVI.00353-10

Experimental method

X-RAY DIFFRACTION (2.8 Å)