SARS-CoV-2 Mutation Detail Information

Virus Mutation SARS-CoV-2 Mutation E290A


Basic Characteristics of Mutations
Mutation Site E290A
Mutation Site Sentence In this context, it is worth noting that a predominantly monomeric form of MPro (MProM, with substitutions E290A and R298A) also exhibits a Tm nearly identical to that of MProWT.
Mutation Level Amino acid level
Mutation Type Nonsynonymous substitution
Gene/Protein/Region Mpro
Standardized Encoding Gene ORF1a  
Genotype/Subtype -
Viral Reference -
Functional Impact and Mechanisms
Disease COVID-19    
Immune -
Target Gene -
Clinical and Epidemiological Correlations
Clinical Information -
Treatment -
Location -
Literature Information
PMID 37271339
Title Contribution of the catalytic dyad of SARS-CoV-2 main protease to binding covalent and noncovalent inhibitors
Author Kovalevsky A,Aniana A,Coates L,Bonnesen PV,Nashed NT,Louis JM
Journal The Journal of biological chemistry
Journal Info 2023 Jul;299(7):104886
Abstract The effect of mutations of the catalytic dyad residues of SARS-CoV-2 main protease (MPro(WT)) on the thermodynamics of binding of covalent inhibitors comprising nitrile [nirmatrelvir (NMV), NBH2], aldehyde (GC373), and ketone (BBH1) warheads to MPro is examined together with room temperature X-ray crystallography. When lacking the nucleophilic C145, NMV binding is approximately 400-fold weaker corresponding to 3.5 kcal/mol and 13.3 degrees C decrease in free energy (DeltaG) and thermal stability (T(m)), respectively, relative to MPro(WT). The H41A mutation results in a 20-fold increase in the dissociation constant (K(d)), and 1.7 kcal/mol and 1.4 degrees C decreases in DeltaG and T(m), respectively. Increasing the pH from 7.2 to 8.2 enhances NMV binding to MPro(H41A), whereas no significant change is observed in binding to MPro(WT). Structures of the four inhibitor complexes with MPro(1-304/C145A) show that the active site geometries of the complexes are nearly identical to that of MPro(WT) with the nucleophilic sulfur of C145 positioned to react with the nitrile or the carbonyl carbon. These results support a two-step mechanism for the formation of the covalent complex involving an initial non-covalent binding followed by a nucleophilic attack by the thiolate anion of C145 on the warhead carbon. Noncovalent inhibitor ensitrelvir (ESV) exhibits a binding affinity to MPro(WT) that is similar to NMV but differs in its thermodynamic signature from NMV. The binding of ESV to MPro(C145A) also results in a significant, but smaller, increase in K(d) and decrease in DeltaG and T(m), relative to NMV.
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.