Unveiling the Catalytic Mechanism of Abl1 Kinase: A Single-Magnesium Ion Pathway for Phosphoryl Transfer.

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Tác giả: Sinisa Bjelic, Ran Friedman, Stella Hernandez Maganhi

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: United States : Biochemistry , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 722832

Abl1, a nonreceptor tyrosine kinase closely related to Src kinase, regulates critical cellular processes like proliferation, differentiation, cytoskeletal dynamics, and response to environmental cues through phosphorylation-driven activation. Dysregulation places it centrally in the oncogenic pathway leading to blood cancers. making it an ideal drug target for small molecule inhibitors. We sought to understand the underlying mechanism of the phosphoryl-transfer step from the ATP molecule to the substrate tyrosine, as carried out by the Abl1 enzyme. By calculating free energy profiles for the reaction using the empirical valence bond representation of the reacting fragments paired with molecular dynamics and free energy perturbation calculations, a combination of several plausible reaction pathways, ATP conformations, and the number of magnesium ion cofactors have been investigated. For the best-catalyzed pathway, which proceeds through a dissociative mechanism with a single magnesium ion situated in Site I, a close agreement was reached with the experimentally determined catalytic rates. We conclude that the catalytic mechanism in Abl1 requires one magnesium ion for efficient catalysis, unlike other kinases, where two ions are utilized. A better overall understanding of the phosphoryl-transfer reactions in Abl1 can be used for type-I inhibitor development and generally contributes to a comprehensive overview of the mechanism for ATP-driven reactions.
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