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Literature summary extracted from

  • Deredge, D.; Li, J.; Johnson, K.A.; Wintrode, P.L.
    Hydrogen/deuterium exchange kinetics demonstrate long range allosteric effects of thumb site 2 inhibitors of hepatitis C viral RNA-dependent RNA polymerase (2016), J. Biol. Chem., 291, 10078-10088.
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
2.7.7.48 drug development the enzyme is a target for inhibitor design Hepacivirus C

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.7.7.48 filibuvir
-
 Hepacivirus C
2.7.7.48 GS-9669
-
 Hepacivirus C
2.7.7.48 lomibuvir
-
 Hepacivirus C
2.7.7.48 additional information non-nucleoside analogue inhibitors are being developed as part of a multidrug regiment to treat hepatitis C viral infections. Particularly promising are inhibitors that bind to the surface of the thumb domain of the viral RNA-dependent RNA polymerase. Kinetic analysis shows that non-nucleoside inhibitors binding to thumb site-2 (NNI2) do not block initiation or elongation of RNA synthesis, rather, they block the transition from the initiation to elongation, which is thought to proceed with significant structural rearrangement of the enzyme-RNA complex. Mapping of the effect of three NNI2 inhibitors on the conformational dynamics of the enzyme using hydrogen/deuterium exchange kinetics, overview. NNI2 inhibitors act through long range allosteric effects, revealing important conformational changes underlying normal polymerase function. Losses in conformational dynamics upon binding of NNI2s is correlated with inhibitor potency Hepacivirus C

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
2.7.7.48 Mg2+ required Hepacivirus C

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.7.7.48 nucleoside triphosphate + RNAn Hepacivirus C
-
 diphosphate + RNAn+1
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.7.7.48 Hepacivirus C
-
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.7.7.48 nucleoside triphosphate + RNAn
-
 Hepacivirus C diphosphate + RNAn+1
-
 ?

Synonyms

EC Number Synonyms Comment Organism
2.7.7.48 NS5B
-
 Hepacivirus C
2.7.7.48 RNA-dependent RNA polymerase
-
 Hepacivirus C

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
2.7.7.48 25
-
 assay at Hepacivirus C

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
2.7.7.48 7.4
-
 assay at Hepacivirus C