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Daily Signal June 09, 2026 · 10 min read

Issue #126: Defining Active Conformations from Substrate-Bound Structures Enables Active-State AlphaFold2 Modeling of All 437 Human Catalytic Protein Kinase Domains.

Protein Design Digest #126: BA-Pred and RMSD-Pred: Integrated Graph Neural Network Models for Accura…

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Defining Active Conformations from Substrate-Bound Structures Enables Active-State AlphaFold2 Modeling of All 437 Human Catalytic Protein Kinase Domains.

Humans have 437 catalytically competent protein kinase domains with a typical kinase fold resembling Protein Kinase A. The active form of a kinase must satisfy requirements for binding ATP, magnesium, and substrate. From structural bioinformatics analysis of 248 crystal structures of 54 kinase-substrate complexes, we derived structural criteria for the active form of typical protein kinases. We include well-known requirements on the DFG motif of the activation loop (ActLoop) and the N-terminal domain salt-bridge, but also on substrate-compatible states of the ActLoop N-terminal and C-terminal segments. With these criteria, only 123 of the 437 human catalytic protein kinases (cPKs) have active forms in the Protein Data Bank. Because the active forms are needed for understanding substrate specificity and mutational effects on catalytic activity in cancer and other diseases, we used AlphaFold2 to produce active models of all 437 human cPKs. This was accomplished with PDB templates that resemble substrate-bound structures, shallow sequence alignments of close paralogs/orthologs, and application of the active-kinase criteria to the output models. We selected models for each kinase based on (intramolecular) ActLoop ipSAE scores and show that the highest scoring models tend to have the lowest RMSD to substrate-bound PDB structures. In a benchmark of 117 kinases, 92% have a highest-scoring AlphaFold2 model with backbone RMSD < 2.0 Å to their benchmark active structure. Models for all 437 cPKs are available at https://dunbrack.fccc.edu/kincore/activemodels. We believe they may be useful for interpreting mutation-induced constitutive activity and as templates for modeling substrate and inhibitor binding to the active-state.

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Also Worth Reading

Computational Assessment of Phytochemical Inhibitors of Cytochrome P450 2E1 (CYP2E1) Implicated in Hepatotoxicity: Comparative Molecular Docking and Interaction Analysis Using Silymarin as a Benchmark

Abstract Liver diseases remain a major global health challenge, often driven by oxidative stress and reactive metabolites generated during xenobiotic metabolism. Cytochrome P450 2E1 (CYP2E1) plays a central role in hepatotoxicity through the bioactivation of toxic compounds and excessive production of reactive oxygen species. This study aimed to evaluate the inhibitory potential of selected phytochemicals (curcumin, quercetin, and kaempferol) against CYP2E1 using molecular docking, with silymarin as a benchmark compound. Molecular docking was performed using SwissDock, while UCSF Chimera was used for three-dimensional visualization and interaction confirmation. BIOVIA Discovery Studio Visualizer was employed for detailed 2D interaction profiling, including hydrogen bonding and hydrophobic interaction analysis. Binding affinities were evaluated based on estimated free energy values (ΔG), and interaction patterns were analyzed to assess ligand stability within the CYP2E1 active site. Results revealed that curcumin exhibited the strongest binding affinity (− 6.9889 kcal/mol), outperforming the benchmark ligand silymarin (− 6.5559 kcal/mol), followed by kaempferol (− 6.3145 kcal/mol) and quercetin (− 6.0048 kcal/mol). Curcumin also formed the highest number of hydrogen bonds and demonstrated favorable hydrophobic and short-range interactions within the active site. These combined interactions suggest strong ligand–enzyme stability and effective binding within the CYP2E1 catalytic pocket. On the whole curcumin demonstrated the most promising inhibitory potential against CYP2E1 among the evaluated phytochemicals, suggesting its possible role as a natural hepatoprotective agent. However, further molecular dynamics simulations, in vitro enzymatic studies, and in vivo validation are required to confirm its therapeutic efficacy.

Exploring the mechanism of saffron in treating viral myocarditis using network pharmacology and molecular docking.

Viral myocarditis (VM) is a cardiovascular disorder that can lead to heart failure and cardiogenic shock. Saffron, a traditional Chinese medicinal herb, has shown therapeutic potential against VM in numerous studies. However, the mechanisms through which saffron exerts its effects on VM remain poorly understood. Thus, this study aimed to elucidate the active compounds, molecular targets, and signaling pathways involved in saffron’s therapeutic action against VM by employing network pharmacology and molecular docking approaches. The active compounds and corresponding targets of saffron were retrieved from the Traditional Chinese Medicine Systems Pharmacology database. VM-associated targets were sourced from the GeneCards database. Overlapping targets between saffron and VM were then identified. Protein-protein interaction networks were established and analyzed utilizing the STRING platform and Cytoscape software to determine core targets. Furthermore, gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses were carried out utilizing Bioconductor in R to explore the potential biological activities and signaling pathways through which saffron may act against VM. Finally, molecular docking and model visualization were carried out using AutoDock Tools and PyMOL open-source software. From the database, we identified 4 active compounds in saffron with potential effects against VM: crocetin, isorhamnetin, kaempferol, and quercetin. A total of 60 corresponding targets were observed, with TNF, IL-6, IL-1β, CXCL8, and JUN emerging as core targets. Kyoto encyclopedia of genes and genomes enrichment analysis revealed 155 regulatory signaling pathways, among which the TNF, AGE-RAGE, and IL-17 signaling pathways, lipid metabolism, and atherosclerosis were the most prominent. Molecular docking results indicated that quercetin showed the strongest binding affinity toward IL-1β and CXCL8. The therapeutic effect of saffron against VM is not driven by a single factor, but rather involves multiple active compounds, targets, and signaling pathways.

Investigation of in vitro anticancer and antioxidant activities of various extracts of Bayramiç Beyazı nectarine, and molecular docking, molecular dynamics simulation, and protein-protein interaction network

Nectarine (Prunus persica var. nucipersica), due to its high phenolic content and antioxidant properties, holds significance for human health. The aim of this study was to evaluate the in vitro anticancer and antioxidant effects of the extracts obtained from the fruit and kernel of “Bayramiç Beyazı” nectarine, a geographically indicated fruit grown in Bayramiç district of Çanakkale. The anticancer effects of the methanol and aqueous ethanol extracts were evaluated on breast and colon cancer cell lines. Apoptotic fragmentation and mitochondrial membrane potential of fruit and kernel extracts were examined under fluorescence microscopy. Antioxidant activity and phenolic content were determined using DPPH, ABTS, and Folin-Ciocalteu (F-C) methods, respectively. Kernel extract has the highest antioxidant activity (DPPH IC₅₀= 0.15 ± 0.001 mg/mL). The fruit methanol, aqueous ethanol, and kernel aqueous ethanol extracts significantly reduced the fluorescent intensity of the cells. A combination study was conducted between the extracts and doxorubicin. Molecular docking and molecular dynamics (MD) simulation studies of some of the identified components were performed using the Glide/SP and Desmond against a drug target PRK1. The highest binding affinity with quercetin for targeting PRK1 was calculated as -8.789 kcal/mol. The average RMSD values were calculated between 3.43 ± 0.31 and 2.22 ± 0.30 Å throughout 500 ns MD simulations. A protein-protein interaction network analysis was performed for PRK1 using a systems biology approach to identify the highest scoring predicted proteins such as RHOA, MAP2K3, and MEFV. The investigation of the in vitro anticancer effects of “Bayramiç Beyazı” extracts and combined in silico analyses were carried out for the first time, and the outcomes of this study have promising potential for future studies.

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Humans have 437 catalytically competent protein kinase domains with a typical kinase fold resembling Protein Kinase A. Read more →

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