A Conserved Pocket in the Dengue Virus Polymerase Identified through Fragment-based Screening.
J Biol Chem
; 291(16): 8541-8, 2016 Apr 15.
Article
em En
| MEDLINE
| ID: mdl-26872970
ABSTRACT
We performed a fragment screen on the dengue virus serotype 3 RNA-dependent RNA polymerase using x-ray crystallography. A screen of 1,400 fragments in pools of eight identified a single hit that bound in a novel pocket in the protein. This pocket is located in the polymerase palm subdomain and conserved across the four serotypes of dengue virus. The compound binds to the polymerase in solution as evidenced by surface plasmon resonance and isothermal titration calorimetry analyses. Related compounds where a phenyl is replaced by a thiophene show higher affinity binding, indicating the potential for rational design. Importantly, inhibition of enzyme activity correlated with the binding affinity, showing that the pocket is functionally important for polymerase activity. This fragment is an excellent starting point for optimization through rational structure-based design.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Virais
/
RNA Polimerases Dirigidas por DNA
/
Vírus da Dengue
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2016
Tipo de documento:
Article