RESUMO
Mitogen-activated protein kinase kinase 1 (MAPK kinase 1, MEK1) is a key kinase in the mitogen-activated protein kinase (MAPK) signaling pathway. MEK1 mutations have been reported to lead to abnormal activation that is closely related to the malignant growth and spread of various tumors, making it an important target for cancer treatment. Targeting MEK1, four small-molecular drugs have been approved by the FDA, including Trametinib, Cobimetinib, Binimetinib, and Selumetinib. Recently, a study showed that modification with dehydroalanine (Dha) can also lead to abnormal activation of MEK1, which has the potential to promote tumor development. In this study, we used molecular dynamics simulations and metadynamics to explore the mechanism of abnormal activation of MEK1 caused by the Dha modification and predicted the inhibitory effects of four FDA-approved MEK1 inhibitors on the Dha-modified MEK1. The results showed that the mechanism of abnormal activation of MEK1 caused by the Dha modification is due to the movement of the active segment, which opens the active pocket and exposes the catalytic site, leading to sustained abnormal activation of MEK1. Among four FDA-approved inhibitors, only Selumetinib clearly blocks the active site by changing the secondary structure of the active segment from α-helix to disordered loop. Our study will help to explain the mechanism of abnormal activation of MEK1 caused by the Dha modification and provide clues for the development of corresponding inhibitors.
Assuntos
Alanina , MAP Quinase Quinase 1 , Simulação de Dinâmica Molecular , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 1/química , Alanina/análogos & derivados , Alanina/química , Alanina/farmacologia , Alanina/metabolismo , Humanos , Domínio Catalítico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Ativação Enzimática/efeitos dos fármacos , Benzimidazóis/farmacologia , Benzimidazóis/químicaRESUMO
Short peptides that can respond to external stimuli have been considered as the preferred building blocks to construct hydrogels for biomedical applications. In particular, photoresponsive peptides that are capable of triggering the formation of hydrogels upon light irradiation allow the properties of hydrogels to be changed remotely by precise and localized actuation. Here, we used the photochemical reaction of the 2-nitrobenzyl ester group (NB) to develop a facile and versatile strategy for constructing photoactivated peptide hydrogels. The peptides with high aggregation propensity were designed as hydrogelators, which were photocaged by a positively charged dipeptide (KK) to provide strong charge repulsion and prevent self-assembly in water. Light irradiation led to the removal of KK and triggered the self-assembly of peptides and the formation of hydrogel. Light stimulation endows spatial and temporal control, which enables the formation of hydrogel with precisely tunable structure and mechanical properties. Cell culture and behavior study indicated that the optimized photoactivated hydrogel was suitable for 2D and 3D cell culture, and its photocontrollable mechanical strength could regulate the spreading of stem cells on its surface. Therefore, our strategy provides an alternative way to construct photoactivated peptide hydrogels with wide applications in biomedical areas.