ZIKV Mutation Detail Information

Virus Mutation ZIKV Mutation A125C


Basic Characteristics of Mutations
Mutation Site A125C
Mutation Site Sentence To experimentally verify the existence of this allosteric mechanism, we expressed and purified the Ala125Cys mutant of ZIKV NS2B-NS3pro and demonstrated that this variant is inhibited by the thiol-containing chemical probes 5,5'-dithiobis-(2-nitrobenzoic acid) and aldrithiol, which do not affect the activity of the wild-type protein.
Mutation Level Amino acid level
Mutation Type Nonsynonymous substitution
Gene/Protein/Region NS2B-NS3pro
Standardized Encoding Gene
Genotype/Subtype -
Viral Reference KU729217.2
Functional Impact and Mechanisms
Disease -
Immune -
Target Gene -
Clinical and Epidemiological Correlations
Clinical Information -
Treatment -
Location Brazil
Literature Information
PMID 35128923
Title Characterization of an Allosteric Pocket in Zika Virus NS2B-NS3 Protease
Author Santos NP,Santos LH,Torquato Quezado de Magalhaes M,Lei J,Hilgenfeld R,Salgado Ferreira R,Bleicher L
Journal Journal of chemical information and modeling
Journal Info 2022 Feb 28;62(4):945-957
Abstract The NS2B-NS3 protease from Zika virus (ZIKV NS2B-NS3pro) cleaves the viral polyprotein, being essential for its replication and a therapeutic target. Inhibitors that target the active site of ZIKV NS2B-NS3pro have been developed, but they tend to have unfavorable pharmacokinetic properties due to their highly positive charge. Thus, the characterization of allosteric sites in this protease provides new strategies for inhibitor development. Here, we characterized a new allosteric pocket in ZIKV NS2B-NS3pro, analogous to the one previously described for the dengue virus protease. Molecular dynamics simulations indicate the presence of cavities around the residue Ala125, sampling protein conformations in which they are connected to the active site. This link between the residue Ala125 and the active site residues was reinforced by correlation network analysis. To experimentally verify the existence of this allosteric mechanism, we expressed and purified the Ala125Cys mutant of ZIKV NS2B-NS3pro and demonstrated that this variant is inhibited by the thiol-containing chemical probes 5,5'-dithiobis-(2-nitrobenzoic acid) and aldrithiol, which do not affect the activity of the wild-type protein. Inhibition of the mutant protein is reversed by the addition of strong reducing agents, supporting the involvement of Cys125 in covalent bond formation and enzyme inhibition. Together, our results provide experimental evidence for an allosteric pocket in ZIKV NS2B-NS3pro, in the region around Ala125, and computational insights on the structural connection between this region and the enzyme active site.
Sequence Data -
Mutation Information
Note
Basic Characteristics of Mutations
  • Mutation Site: The specific location in a gene or protein sequence where a change occurs.
  • Mutation Level: The level at which a mutation occurs, including the nucleotide or amino acid level.
  • Mutation Type: The nature of the mutation, such as missense mutation, nonsense mutation, synonymous mutation, etc.
  • Gene/Protein/Region: Refers to the specific region of the virus where the mutation occurs. Including viral genes, viral proteins, or a specific viral genome region. If the article does not specifically indicate the relationship between the mutation and its correspondence, the main
  • Gene/Protein/Region studied in the article is marked.
  • Genotype/Subtype: Refers to the viral genotype or subtype where the mutation occurs. If the article does not specifically indicate the relationship between the mutation and its correspondence, the main Genotype/Subtype studied in the article is marked.
  • Viral Reference: Refers to the standard virus strain used to compare and analyze viral sequences.
Functional Impact and Mechanisms
  • Disease: An abnormal physiological state with specific symptoms and signs caused by viral infection.
  • Immune: The article focuses on the study of mutations and immune.
  • Target Gene: Host genes that viral mutations may affect.
Clinical and Epidemiological Correlations
  • Clinical Information: The study is a clinical or epidemiological study and provides basic information about the population.
  • Treatment: The study mentioned a certain treatment method, such as drug resistance caused by mutations. If the study does not specifically indicate the relationship between mutations and their correspondence treatment, the main treatment studied in the article is marked.
  • Location: The source of the research data.
Literature Information
  • Sequence Data: The study provides the data accession number.