International journal of biological macromolecules · 2025
Integrating single-cell transcriptomics, molecular docking, and dynamics simulations to characterize protein kinase X-linked mechanisms in osteosarcoma.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Zhang Zongye, Sha Zhi, Liu Zhendong, Cheng Xingbo, Hou Zhenxing, Wang Dongdong, Zhang Zhichang, Gao Yanzheng
Аннотация
BACKGROUND: Osteosarcoma (OS) progression is linked to kinase allostery dysregulation, but PRKX's allosteric role remains unknown. We aimed to decode PRKX's activation mechanism and assess its clinical potential as a biomarker and therapeutic target.
METHODS: Differential expression analysis confirmed PRKX's oncogenic role. Using single-cell RNA-seq (GSE152048) with spatiotemporal trajectory analysis, we delineated PRKX-CDC37 interactions. PRKX-knockdown via siRNA suppressed proliferation, invasion, and colony formation in vitro. Based on the AlphaFold-predicted PRKX-CDC37 complex, we performed molecular docking followed by explicit-solvent 100-ns MD simulations to evaluate inhibitor binding.
RESULTS: Multi-omics revealed PRKX-CDC37 spatiotemporal co-expression driving early TME differentiation. Ergotamine (ΔG = -11.6 kcal/mol) competitively bound PRKX's catalytic pocket via a tripartite H-bond network centered on HIS161. MD simulations demonstrated ≥95 % occupancy H-bonds and 28.6 % SASA reduction, confirming ergotamine as the lead PRKX-CDC37 inhibitor with nanomolar-scale affinity.
CONCLUSION: PRKX drives OS via a CDC37-mediated allosteric pathway, with Pocket-3 (HIS161) as a therapeutic target. Ergotamine validates PRKX-CDC37 inhibition, providing a framework for anti-OS drug design.
METHODS: Differential expression analysis confirmed PRKX's oncogenic role. Using single-cell RNA-seq (GSE152048) with spatiotemporal trajectory analysis, we delineated PRKX-CDC37 interactions. PRKX-knockdown via siRNA suppressed proliferation, invasion, and colony formation in vitro. Based on the AlphaFold-predicted PRKX-CDC37 complex, we performed molecular docking followed by explicit-solvent 100-ns MD simulations to evaluate inhibitor binding.
RESULTS: Multi-omics revealed PRKX-CDC37 spatiotemporal co-expression driving early TME differentiation. Ergotamine (ΔG = -11.6 kcal/mol) competitively bound PRKX's catalytic pocket via a tripartite H-bond network centered on HIS161. MD simulations demonstrated ≥95 % occupancy H-bonds and 28.6 % SASA reduction, confirming ergotamine as the lead PRKX-CDC37 inhibitor with nanomolar-scale affinity.
CONCLUSION: PRKX drives OS via a CDC37-mediated allosteric pathway, with Pocket-3 (HIS161) as a therapeutic target. Ergotamine validates PRKX-CDC37 inhibition, providing a framework for anti-OS drug design.