Literature summary for 3.1.26.13 extracted from

Chung, S.; Himmel, D.; Jiang, J.; Wojtak, K.; Bauman, J.; Rausch, J.; Wilson, J.; Beutler, J.; Thomas, C.; Arnold, E.; Le Grice, S.
Synthesis, activity, and structural analysis of novel alpha-hydroxytropolone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H (2011), J. Med. Chem., 54, 4462-4473.

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Cloned(Commentary)

Cloned (Comment)	Organism
expression of His6-tagged p66/p51 HIV-1 reverse transcriptase p51/p66 52A variant C280S, the p66 subunit also contains the mutations K172A and K173A	Human immunodeficiency virus 1

Crystallization (Commentary)

Crystallization (Comment)	Organism
purified p66/p51 HIV-1 reverse transcriptase 52A variant in complex with inhibitors manicol and TMC278, 0.0012 ml of 20 mg/mL protein in 9.2 mM Tris, pH 8.0, 68.7 mM NaCl, 3.6 mM manganese sulfate, 0.7 mM tris(2-carboxyethyl) phosphine, 0.27% w/v, beta-ocytl glucopyranoside, 7% v/v DMSO, 0.9 mM manicol, and 0.7 mM TMC278, mixed with 0.0012 ml of reservoir solution containing 50 mM HEPES pH 7.5, 100 mM ammonium sulfate, 15 mM manganese sulfate, 10 mM spermine, 5 mM TCEP, and 11% w/w PEG 8000, X-ray diffraction structure determination and analysis at 2.7 A resolution, modeling	Human immunodeficiency virus 1

Crystallization (Comment)

Organism

purified p66/p51 HIV-1 reverse transcriptase 52A variant in complex with inhibitors manicol and TMC278, 0.0012 ml of 20 mg/mL protein in 9.2 mM Tris, pH 8.0, 68.7 mM NaCl, 3.6 mM manganese sulfate, 0.7 mM tris(2-carboxyethyl) phosphine, 0.27% w/v, beta-ocytl glucopyranoside, 7% v/v DMSO, 0.9 mM manicol, and 0.7 mM TMC278, mixed with 0.0012 ml of reservoir solution containing 50 mM HEPES pH 7.5, 100 mM ammonium sulfate, 15 mM manganese sulfate, 10 mM spermine, 5 mM TCEP, and 11% w/w PEG 8000, X-ray diffraction structure determination and analysis at 2.7 A resolution, modeling

Human immunodeficiency virus 1

Protein Variants

Protein Variants	Comment	Organism
C280S/K172A/K173A	p66/p51 HIV-1 reverse transcriptase 52A mutant variant, the mutation C208S resides in both subunits, the p66 subunit also contains the mutations K172A and K173A	Human immunodeficiency virus 1

Inhibitors

Inhibitors	Comment	Organism
(2S)-5,7-dihydroxy-2-(2-hydroxy-1-(phenylsulfonyl)propan-2-yl)-9-methyl-3,4-dihydro-1H-benzo[7]annulen-6(2H)-one	-	Human immunodeficiency virus 1
1,3,4,5-tetrahydrogalloylapitol	-	Human immunodeficiency virus 1
2,7-dihydroxy-4-isopropyl-cyclohepta-2,4,6-triene	i.e. beta-thujaplicinol	Human immunodeficiency virus 1
2-(1,2-dihydroxy-1-methyl-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	-	Human immunodeficiency virus 1
2-(1-benzylamino-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	-	Human immunodeficiency virus 1
2-(2-benzylsulfanyl-1-hydroxy-1-methyl-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	-	Human immunodeficiency virus 1
2-(2-diethylamino-1-hydroxy-1-methyl-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	-	Human immunodeficiency virus 1
2-(2-ethanesulfonyl-1-hydroxy-1-methyl-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	-	Human immunodeficiency virus 1
2-(2-ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	-	Human immunodeficiency virus 1
2-[2-(2-fluoro-benzylamino)-1-hydroxy-1-methyl-ethyl]-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	-	Human immunodeficiency virus 1
3,9,11,14,15-pentahydroxy-7-methoxy-10-methyl-5,6-dihydrobenzo[9,10]tetrapheno[2,3-c]furan-1,8,13(3H)-trione	-	Human immunodeficiency virus 1
4-[[4-([4-[(E)-2-cyanovinyl]-2,6-dimethylphenyl]amino)pyrimidin-2-yl]amino]benzonitrile	i.e. TMC278 or rilpivirine, enzyme-bound structure, overview	Human immunodeficiency virus 1
5,7-dihydroxy-2-(1-hydroxy-1-methyl-2-phenylaminoethyl)-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	-	Human immunodeficiency virus 1
5,7-dihydroxy-2-(1-hydroxy-1-methyl-2-phenylsulfanylethyl)-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	-	Human immunodeficiency virus 1
5,7-dihydroxy-2-(1-hydroxy-1-methyl-2-piperidin-1-ylethyl)-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	-	Human immunodeficiency virus 1
5,7-dihydroxy-2-(1-hydroxy-2-imadazol-1-yl-1-methyl ethyl)-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	-	Human immunodeficiency virus 1
5,7-dihydroxy-2-(1-hydroxy-ethyl)-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	-	Human immunodeficiency virus 1
5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	i.e. manicol, the alpha-hydroxytroplone potently and specifically inhibits HIV RT ribonuclease H, enzyme-bound structure, overview	Human immunodeficiency virus 1
additional information	no inhibition by 5,7-dihydroxy-2-(1-hydroxy-1-methyl-2-piperidin-1-ylethyl)-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one, 5,7-dihydroxy-2-(1-hydroxy-2-imadazol-1-yl-1-methyl ethyl)-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one, 2-(2-diethylamino-1-hydroxy-1-methyl-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one, and 2-(1-benzylamino-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one	Human immunodeficiency virus 1

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mn2+	modeling of the HIV-1 RNase H domain in complex with an inhibitor and two Mn2+ cations from crystal structure of manicol-bound enzyme	Human immunodeficiency virus 1

Organism

Organism	UniProt	Comment	Textmining
Human immunodeficiency virus 1	-	HIV-1	-

Purification (Commentary)

Purification (Comment)	Organism
recombinant His6-tagged p66/p51 HIV-1 reverse transcriptase 52A variant C280S by nickel affinity chromatography, the tag is cleaved by HRV14 3C protease	Human immunodeficiency virus 1

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
additional information	substrate is 18-nucleotide 3'-fluourescein-labeled RNA annealed to a complementary 18-nucleotide 5'-dabsyl-labeled DNA	Human immunodeficiency virus 1	?	-	?

Subunits

Subunits	Comment	Organism
dimer	-	Human immunodeficiency virus 1

Synonyms

Synonyms	Comment	Organism
human immunodeficiency virus reverse transcriptase-associated ribonuclease H	-	Human immunodeficiency virus 1
ribonuclease H	-	Human immunodeficiency virus 1
RNase H	-	Human immunodeficiency virus 1

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
37	-	assay at	Human immunodeficiency virus 1

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
8	-	assay at	Human immunodeficiency virus 1

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor
0.00024	-	pH 8.0, 37°C	Human immunodeficiency virus 1	2-(2-ethanesulfonyl-1-hydroxy-1-methyl-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one
0.00038	-	pH 8.0, 37°C	Human immunodeficiency virus 1	2-(2-ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one
0.0005	-	pH 8.0, 37°C	Human immunodeficiency virus 1	2-(2-diethylamino-1-hydroxy-1-methyl-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one
0.00051	-	pH 8.0, 37°C	Human immunodeficiency virus 1	(2S)-5,7-dihydroxy-2-(2-hydroxy-1-(phenylsulfonyl)propan-2-yl)-9-methyl-3,4-dihydro-1H-benzo[7]annulen-6(2H)-one
0.00068	-	pH 8.0, 37°C	Human immunodeficiency virus 1	5,7-dihydroxy-2-(1-hydroxy-ethyl)-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one
0.00082	-	pH 8.0, 37°C	Human immunodeficiency virus 1	5,7-dihydroxy-2-(1-hydroxy-1-methyl-2-piperidin-1-ylethyl)-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one
0.00093	-	pH 8.0, 37°C	Human immunodeficiency virus 1	5,7-dihydroxy-2-(1-hydroxy-1-methyl-2-phenylsulfanylethyl)-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one
0.00096	-	pH 8.0, 37°C	Human immunodeficiency virus 1	2-(1-benzylamino-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one
0.0012	-	pH 8.0, 37°C	Human immunodeficiency virus 1	2-[2-(2-fluoro-benzylamino)-1-hydroxy-1-methyl-ethyl]-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one
0.0012	-	pH 8.0, 37°C	Human immunodeficiency virus 1	5,7-dihydroxy-2-(1-hydroxy-1-methyl-2-phenylaminoethyl)-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one
0.0013	-	pH 8.0, 37°C	Human immunodeficiency virus 1	2-(2-benzylsulfanyl-1-hydroxy-1-methyl-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one
0.0019	-	pH 8.0, 37°C	Human immunodeficiency virus 1	2-(1,2-dihydroxy-1-methyl-ethyl)-5,7-dihydroxy-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one
0.00911	-	pH 8.0, 37°C	Human immunodeficiency virus 1	5,7-dihydroxy-2-(1-hydroxy-2-imadazol-1-yl-1-methyl ethyl)-9-methyl-1,2,3,4-tetrahydrobenzocyclohepten-6-one