KSHV Mutation Detail Information

Virus Mutation KSHV Mutation D476A


Basic Characteristics of Mutations
Mutation Site D476A
Mutation Site Sentence A minor Mn2+-induced thermal shift was observed for mutant E550A (Tm of 52.9°C versus 53.9°C, ΔTm of 1.0°C), while we observed a destabilizing effect for pORF29C mutants D476A (Tm of 59.7°C versus 59.1°C, ΔTm of −0.6°C) and E662A (Tm of 57.4°C versus 56.2°C, ΔTm of −1.2°C).
Mutation Level Amino acid level
Mutation Type Nonsynonymous substitution
Gene/Protein/Region ORF29
Standardized Encoding Gene ORF29  
Genotype/Subtype -
Viral Reference -
Functional Impact and Mechanisms
Disease Cell line    
Immune -
Target Gene -
Clinical and Epidemiological Correlations
Clinical Information -
Treatment -
Location -
Literature Information
PMID 30061278
Title Sensitivity of the C-Terminal Nuclease Domain of Kaposi's Sarcoma-Associated Herpesvirus ORF29 to Two Classes of Active-Site Ligands
Author Miller JT,Zhao H,Masaoka T,Varnado B,Cornejo Castro EM,Marshall VA,Kouhestani K,Lynn AY,Aron KE,Xia A,Beutler JA,Hirsch DR,Tang L,Whitby D,Murelli RP,Le Grice SFJ
Journal Antimicrobial agents and chemotherapy
Journal Info 2018 Sep 24;62(10):e00233-18
Abstract Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma, belongs to the Herpesviridae family, whose members employ a multicomponent terminase to resolve nonparametric viral DNA into genome-length units prior to their packaging. Homology modeling of the ORF29 C-terminal nuclease domain (pORF29C) and bacteriophage Sf6 gp2 have suggested an active site clustered with four acidic residues, D(476), E(550), D(661), and D(662), that collectively sequester the catalytic divalent metal (Mn(2+)) and also provided important insight into a potential inhibitor binding mode. Using this model, we have expressed, purified, and characterized the wild-type pORF29C and variants with substitutions at the proposed active-site residues. Differential scanning calorimetry demonstrated divalent metal-induced stabilization of wild-type (WT) and D(661)A pORF29C, consistent with which these two enzymes exhibited Mn(2+)-dependent nuclease activity, although the latter mutant was significantly impaired. Thermal stability of WT and D(661)A pORF29C was also enhanced by binding of an alpha-hydroxytropolone (alpha-HT) inhibitor shown to replace divalent metal at the active site. For the remaining mutants, thermal stability was unaffected by divalent metal or alpha-HT binding, supporting their role in catalysis. pORF29C nuclease activity was also inhibited by two classes of small molecules reported to inhibit HIV RNase H and integrase, both of which belong to the superfamily of nucleotidyltransferases. Finally, alpha-HT inhibition of KSHV replication suggests ORF29 nuclease function as an antiviral target that could be combined with latency-activating compounds as a shock-and-kill antiviral strategy.
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.