Structural Dynamics of Zika Virus NS2B-NS3 Protease Binding to Dipeptide Inhibitors.
Structure
; 25(8): 1242-1250.e3, 2017 08 01.
Article
en En
| MEDLINE
| ID: mdl-28689970
ABSTRACT
The NS2B-NS3 viral protease is an attractive drug target against Zika virus (ZIKV) due to its importance in viral replication and maturation. Here we report the crystal structure of protease in complex with a dipeptide inhibitor, Acyl-KR-aldehyde (compound 1). The aldehyde moiety forms a covalent bond with the catalytic Ser135 of NS3. The Arg and Lys residues in the inhibitor occupy the S1 and S2 sites of the protease, respectively. Nuclear magnetic resonance studies demonstrate that the complex is in the closed conformation in solution. The chemical environment of residues surrounding the active site is sensitive to the bound inhibitor as demonstrated by the comparison with two other non-covalent dipeptides, Acyl-K-Agmatine (compound 2) and Acyl-KR-COOH (compound 3). Removing the aldehyde moiety in 1 converts the binding mode from a slow to a fast exchange regime. The structural dynamics information obtained in this study will guide future drug discovery against ZIKV and other flaviviruses.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antivirales
/
Inhibidores de Proteasas
/
Proteínas no Estructurales Virales
/
Dipéptidos
Idioma:
En
Revista:
Structure
Asunto de la revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
BIOTECNOLOGIA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Singapur