M⁶A modification is the most common internal modification of messenger RNA in eukaryotes, and the disorder of m⁶A can trigger cancer progression. The GGACU is considered the most frequent consensus sequence of target transcripts which have a GGAC m⁶A core motif. Newly identified m⁶A ‘readers’ insulin-like growth factor 2 mRNA-binding proteins modulate gene expression by binding to the m⁶A binding sites of target mRNAs, thereby affecting various cancer-related processes. The dynamic impact of the methylation at m⁶A within the GGAC motif on human IGF2BPs has not been investigated at the structural level. In this study, through in silico analysis, we mapped IGF2BPs binding sites for the GGm⁶AC RNA core motif of target mRNAs. Subsequent molecular dynamics simulation analysis at 400 ns revealed that only the KH4 domain of IGF2BP1, containing the 503GKGG506 motif and its periphery residues, was involved in the interaction with the GGm⁶AC backbone. Meanwhile, the methyl group of m⁶A is accommodated by a shallow hydrophobic cradle formed by hydrophobic residues. Interestingly, in IGF2BP2 and IGF2BP3 complexes, the RNA was observed to shift from the KH4 domain to the KH3 domain in the simulation at 400 ns, indicating a distinct dynamic behavior. This suggests a conformational stabilization upon binding, likely essential for the functional interactions involving the KH3-4 domains. These findings highlight the potential of targeting IGF2BPs’ interactions with m⁶A modifications for the development of novel oncological therapies.

Asthma is a chronic inflammatory airway disease influenced by both genetic and environmental factors. Recent insights have underscored the pivotal role of epigenetic regulation in the pathogenesis and heterogeneity of asthma. This review focuses on key epigenetically important regulators categorized as writers, erasers, and readers that govern DNA methylation, histone modifications, and RNA modifications. These proteins modulate gene expression without altering the underlying DNA sequence, thereby influencing immune responses, airway remodeling, and disease severity. We highlight the structural and functional dynamics of histone acetyltransferases (e.g., p300/CBP), histone deacetylases (e.g., SIRT family), DNA methyltransferases (DNMT1, DNMT3A), demethylases (TET1), and methyl-CpG-binding proteins (MBD2) in shaping chromatin accessibility and transcriptional activity. Additionally, the m6A RNA modification machinery including METTL3, METTL14, FTO, YTHDF1/2, IGF2BP2, and WTAP is explored for its emerging significance in regulating post-transcriptional gene expression during asthma progression. Structural characterizations of these proteins reveal conserved catalytic domains and interaction motifs, mirroring their respective families such as SIRTs, p300/CBP, DNMT1/3A, and YTHDF1/2 critical to their epigenetic functions, offering mechanistic insight into their roles in airway inflammation and immune modulation. By elucidating these pathways, this review provides a framework for the development of epigenetic biomarkers and targeted therapies. Future directions emphasize phenotype-specific epigenomic profiling and structure-guided drug design to enable precision medicine approaches in asthma management.

P21-activated kinases (PAKs) are serine/threonine protein kinases that are subdivided into two groups on the basis of their domain architecture: group-I (PAK1–3) and group-II (PAK4–6). PAKs are considered as attractive drug targets that play vital role in cell proliferation, survival, motility, angiogenesis and cytoskeletal dynamics. In current study, molecular dynamics simulation-based comparative residual contributions and differential transitions were monitored in both active and inactive states of human PAK homologs for therapeutic intervention. Due to their involvement in cancer, infectious diseases, and neurological disorders, it is inevitable to develop novel therapeutic strategies that specifically target PAKs on the basis of their activity pattern. In order to isolate novel inhibitors that are able to bind at the active sites of PAK1 and PAK4, high throughput structure-based virtual screening was performed. Multiple lead compounds were proposed on the basis of their binding potential and targeting region either phosphorylated (active) or unphosphorylated PAK isoform (inactive). Thus, ATP-competitive inhibitors may prove ideal therapeutic choice against PAK family members. The detailed conformational readjustements occurring in the PAKs upon phosphorylation-dephosphorylation events may serve as starting point for devising novel drug molecules that are able to target on activity basis. Overall, the observations of current study may add valuable contribution in the inventory of novel inhibitors that may serve as attractive lead compounds for targeting PAK family members on the basis of activity-based conformational changes.