mTOR Variants Activation Discovers PI3K-like Cryptic Pocket, Expanding Allosteric, Mutant-Selective Inhibitor Designs

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown

Опубликована: Янв. 10, 2025

mTOR plays a crucial role in PI3K/AKT/mTOR signaling. We hypothesized that activation mechanisms driving oncogenesis can advise effective therapeutic designs. To test this, we combined cancer genomic analysis with extensive molecular dynamics simulations of oncogenic variants. observed conformational changes within kinase domain are associated multiple mutational events. The mutations disturb the α-packing formed by kαAL, kα3, kα9, kα9b, and kα10 helices domain, creating cryptic pocket. Its opening correlates catalytic cleft, including active site residues realignment, favoring catalysis. pocket created disrupted coincides allosteric PI3Kα be harmoniously fitted inhibitor RLY-2608, suggesting analogous drugs designed based on RLY-2608 restore packed α-structure, resulting inactive conformation. Our results exemplify knowledge detailed inform innovative development.

Язык: Английский

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Discovery of natural compounds as novel FMS-like tyrosine kinase-3 (FLT3) therapeutic inhibitors for the treatment of acute myeloid leukaemia: an in-silico approach

Aspects of Molecular Medicine, Год журнала: 2024, Номер unknown, С. 100058 - 100058

Опубликована: Ноя. 1, 2024

Язык: Английский

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ERK Allosteric Activation: The Importance of Two Ordered Phosphorylation Events

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 2, 2025

Abstract ERK, a coveted proliferation drug target, is pivotal kinase in the Ras/ERK signaling cascade. Despite this, crucial questions about its activation have not been fully explored on foundational, conformational level. Such include (i) Why ERK’s demands dual phosphorylation ; (ii) What role of each site loop and (iii) Exactly how (ordered) steps affect ensembles , their propensities restriction to narrower range favoring catalytic action . Here we used explicit molecular dynamics simulations study stability changes different stages along process. The initial monophosphorylation event elongates enable successive phosphorylations, which reintroduce stability/compactness through newly formed salt bridges. interactions by are site-dependent, with threonine’s presenting stronger electrostatic compared tyrosine’s. Dual phosphorylated ERKs revealed compact structure allows HRD motif stabilize ATP. We further observe that hinge homodimerization binding responded tri-state code based solely degree (unphosphorylated, monophosphorylated, phosphorylated) loop, confirming can allosterically influence distant regions. Last, our findings indicate threonine as second step necessary for ERK become effectively activated depends order. Collectively, offer allosteric explain why order crucial.

Язык: Английский

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ERK Allosteric Activation: The Importance of Two Ordered Phosphorylation Events

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 169130 - 169130

Опубликована: Апрель 1, 2025

Язык: Английский

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