胃癌におけるO6-メチルグアニン-DNA メチルトランスフェラーゼタンパク質構造変化の原子レベル解析
MGMT (O6-methylguanine-DNA methyltransferase) is a key DNA repair enzyme that reverses alkylating agent-induced mutagenic lesions. This study screened a gastric cancer patient cohort from a population with high dietary exposure to alkylating agents, focusing on an error-prone region of the MGMT gene. Approximately 40% of neoplastic samples carried a missense mutation at codon 151, resulting in a serine-to-isoleucine substitution. Molecular dynamics simulation revealed that this substitution disrupts the recognition domain, substrate-binding site, and selectivity loop, accompanied by significant changes in intramolecular hydrogen bond patterns. Physical-functional clustering of interacting amino acid residues demonstrated that the mutation eliminates stabilizing salt bridges in clusters C3, C4, and C5, causing both local and global destabilization of the MGMT protein and impairing its DNA-binding capacity.
A serine-to-isoleucine substitution at codon 151 alters intramolecular hydrogen bonding and eliminates stabilizing salt bridges in clusters C3, C4, and C5, causing local and global destabilization of the MGMT active site and impairing DNA-repair function.
This is basic research at the cellular or molecular level. For human application, inhalation is the most promising delivery route, but inhalation carries explosion risk and concentration matters (empirical LFL of 10%; high-concentration devices are not recommended).
See also:
https://h2-papers.org/en/papers/26011121