Literature summary for 3.1.26.13 extracted from

Boyer, P.L.; Smith, S.J.; Zhao, X.Z.; Das, K.; Gruber, K.; Arnold, E.; Burke, T.R.; Hughes, S.H.
Developing and evaluating inhibitors against the RNase H active site of HIV-1 reverse transcriptase (2018), J. Virol., 92, e02203-17 .

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Crystallization (Commentary)

Crystallization (Comment)	Organism
HIV-1 reverse transcriptase mutant form RT52A in complex with rilpivirine and an RNase H inhibitor XZ462, hanging drop vapor diffusion method, the crystallization solution contains 10% PEG 8000, 50 mM imidazole, pH 6.8, 10 mM spermine, 15 mM MgSO4, and 100 mM (NH4)2SO4, crystals of the RT-rilpivirine (RPV) complex are soaked for 30 min with 2 mM compound XZ462 in the crystallization solution in presence of 15 mM MgSO4, X-ray diffraction structure determination and analysis at 1.51-2.2 A resolution, molecular replacement using the 1.51 A resolution structure of the HIV-1 RT-rilpivirine complex (PDB ID 4G1Q) as template	Human immunodeficiency virus type 1 group M subtype B

Crystallization (Comment)

Organism

HIV-1 reverse transcriptase mutant form RT52A in complex with rilpivirine and an RNase H inhibitor XZ462, hanging drop vapor diffusion method, the crystallization solution contains 10% PEG 8000, 50 mM imidazole, pH 6.8, 10 mM spermine, 15 mM MgSO4, and 100 mM (NH4)2SO4, crystals of the RT-rilpivirine (RPV) complex are soaked for 30 min with 2 mM compound XZ462 in the crystallization solution in presence of 15 mM MgSO4, X-ray diffraction structure determination and analysis at 1.51-2.2 A resolution, molecular replacement using the 1.51 A resolution structure of the HIV-1 RT-rilpivirine complex (PDB ID 4G1Q) as template

Human immunodeficiency virus type 1 group M subtype B

Protein Variants

Protein Variants	Comment	Organism
G140S/Q148H	site-directed mutagenesis, mutant INSTI	Human immunodeficiency virus type 1 group M subtype B
K70R	site-directed mutagenesis, mutant NRTI	Human immunodeficiency virus type 1 group M subtype B
L100I/K103N	site-directed mutagenesis, mutant NNRTI	Human immunodeficiency virus type 1 group M subtype B
M184V	site-directed mutagenesis, mutant NRTI	Human immunodeficiency virus type 1 group M subtype B
V106A	site-directed mutagenesis, mutant NNRTI	Human immunodeficiency virus type 1 group M subtype B
Y181C	site-directed mutagenesis, mutant NNRTI	Human immunodeficiency virus type 1 group M subtype B
Y188L	site-directed mutagenesis, mutant NNRTI	Human immunodeficiency virus type 1 group M subtype B

Inhibitors

Inhibitors	Comment	Organism
4-((4'-amino-[1,1'-biphenyl]-4-yl)amino)-1-hydroxy-1,8-naphthyridin-2(1H)-one	-	Human immunodeficiency virus type 1 group M subtype B
4-([1,1'-biphenyl]-4-ylamino)-1-hydroxy-1,8-naphthyridin-2(1H)-one	-	Human immunodeficiency virus type 1 group M subtype B
methyl 4-((4'-amino-[1,1'-biphenyl]-4-yl)amino)-1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate	-	Human immunodeficiency virus type 1 group M subtype B
methyl 4-amino-1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate	-	Human immunodeficiency virus type 1 group M subtype B
additional information	development and evaluation of inhibitors against the RNase H active site of HIV-1 reverse transcriptase. The RNase H active site of HIV-1 RT is sufficiently different from the active sites of the two cellular human enzymes, RNase H1 and RNase H2, that compounds can be developed as selective inhibitors of viral RH. Antiviral activities of compounds XZ456, XZ460, XZ462, and MK463 against wild-type enzyme and against HIV-1 vectors that carry well-known INSTI, NNRTI, and NRTI resistance mutations, overview. XZ456 and XZ460 both inhibit these NRTI mutants with efficacies similar to their antiviral activities against wild-type HIV-1. Conversely, the NRTI-resistant mutants cause a 3 to 4fold reduction in susceptibility to XZ462 and MK463. Compounds are tested in viral replication and cytotoxicity assays. For enzyme-inhibitor structural modelling, coordinates of the following retroviral RT-RT inhibitor structures are used: HIV RT-MK1 (PDB ID 3LP0) and HIV RT-MK2 (PDB ID 3LP1). The compounds target the catalytic magnesium ions in the HIV-1 RNase H	Human immunodeficiency virus type 1 group M subtype B

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mg2+	required	Human immunodeficiency virus type 1 group M subtype B

Organism

Organism	UniProt	Comment	Textmining
Human immunodeficiency virus type 1 group M subtype B	P03366	HIV-1	-
Human immunodeficiency virus type 1 group M subtype B BH10	P03366	HIV-1	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
additional information	5' end labeled RNA-DNA heteroduplexe substrates aligned from commercial RNA and DNA oligonucleotides are used	Human immunodeficiency virus type 1 group M subtype B	?	-	?
additional information	5' end labeled RNA-DNA heteroduplexe substrates aligned from commercial RNA and DNA oligonucleotides are used	Human immunodeficiency virus type 1 group M subtype B BH10	?	-	?

Synonyms

Synonyms	Comment	Organism
HIV-1 RH	-	Human immunodeficiency virus type 1 group M subtype B
HIV-1 RNase H	-	Human immunodeficiency virus type 1 group M subtype B
RNase H	-	Human immunodeficiency virus type 1 group M subtype B

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
37	-	assay at	Human immunodeficiency virus type 1 group M subtype B

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
8	-	assay at	Human immunodeficiency virus type 1 group M subtype B

General Information

General Information	Comment	Organism
additional information	for enzyme-inhibitor structural modelling, coordinates of the following retroviral RT-RT inhibitor structures are used: HIV RT-MK1 (PDB ID 3LP0) and HIV RT-MK2 (PDB ID 3LP1)	Human immunodeficiency virus type 1 group M subtype B