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Structural Dynamics of Zika Virus NS2B-NS3 Protease Binding to Dipeptide Inhibitors
- Source :
- Structure. 25:1242-1250.e3
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
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.
- Subjects :
- 0301 basic medicine
Stereochemistry
viruses
medicine.medical_treatment
Plasma protein binding
Molecular Dynamics Simulation
Viral Nonstructural Proteins
Antiviral Agents
03 medical and health sciences
chemistry.chemical_compound
Structural Biology
Catalytic Domain
medicine
Moiety
Protease Inhibitors
Molecular Biology
NS3
Protease
Dipeptide
030102 biochemistry & molecular biology
biology
Chemistry
Protease binding
Serine Endopeptidases
Active site
Dipeptides
Zika Virus
Protease inhibitor (biology)
Molecular Docking Simulation
030104 developmental biology
biology.protein
RNA Helicases
Protein Binding
medicine.drug
Subjects
Details
- ISSN :
- 09692126
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Structure
- Accession number :
- edsair.doi.dedup.....f98fa51f1d08881cf2e6521064dcde7d
- Full Text :
- https://doi.org/10.1016/j.str.2017.06.006