ArticleNature communications2024
Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- A conserved phospho-switch controls receptor kinase SDS2 activation and homeostasis in rice immunity.Science advances · 2026Article
- Non-receptor tyrosine kinase signaling pathways and therapeutic implications.Signal transduction and targeted therapy · 2026Review
- Context-dependent peptide recognition shapes tyrosine kinase substrate specificity beyond consensus motifs.bioRxiv : the preprint server for biology · 2026Article
- AAK1-mediated phosphorylation of PDLIM5 and Talin1 promotes focal adhesion disassembly to accelerate cell migration.Nature communications · 2026Article
- Results of a Large-Scale Study of the Binding of 50 Type II Inhibitors to 348 Kinases: The Role of Protein Reorganization.Journal of medicinal chemistry · 2026Article
- Defining the Active Conformation of Typical Protein Kinase Domains from Substrate-Bound PDB Structures Enables Active-State AlphaFold2 Models for All 437 Human Catalytic Protein Kinases.bioRxiv : the preprint server for biology · 2026Article
- Toward Reconciling the Standard Binding Free Energy of Lenacapavir to HIV-1 Capsid with Experiment: Thermodynamic Effects of Solvent Buffer and Ligand Reorganization.The journal of physical chemistry. B · 2026Article
- Results of a large scale study of the binding of 50 type II inhibitors to 348 kinases: The role of protein reorganization.bioRxiv : the preprint server for biology · 2026Article
- Predicting side chain conformations in folded proteins by AlphaFold: Perspective and challenges.Biophysical journal · 2025Article
- Impact of intrinsically disordered regions and functional disorder hotspots in the human kinome.Briefings in bioinformatics · 2025Article
- Structural insights into allosteric inhibition of HRI kinase by heme binding via HDX-MS.The Biochemical journal · 2025Article
- The fast-evolving FIKK kinase family of Plasmodium falciparum can be inhibited by a single compound.Nature microbiology · 2025Article
- MAST Kinases' Function and Regulation: Insights from Structural Modeling and Disease Mutations.Biomedicines · 2025Article
- Using AlphaFold2 to Predict the Conformations of Side Chains in Folded Proteins.bioRxiv : the preprint server for biology · 2025Article
- A literature review of recent advances in gastric cancer treatment: exploring the cross-talk between targeted therapies.Cancer cell international · 2025Review
- Empowering AlphaFold2 for protein conformation selective drug discovery with AlphaFold2-RAVE.eLife · 2024Article
- A comprehensive exploration of the druggable conformational space of protein kinases using AI-predicted structures.PLoS computational biology · 2024Article
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Abstract
Protein kinases are molecular machines with rich sequence variation that distinguishes the two main evolutionary branches - tyrosine kinases (TKs) from serine/threonine kinases (STKs). Using a sequence co-variation Potts statistical energy model we previously concluded that TK catalytic domains are more likely than STKs to adopt an inactive conformation with the activation loop in an autoinhibitory folded conformation, due to intrinsic sequence effects. Here we investigate the structural basis for this phenomenon by integrating the sequence-based model with structure-based molecular dynamics (MD) to determine the effects of mutations on the free energy difference between active and inactive conformations, using a thermodynamic cycle involving many (n = 108) protein-mutation free energy perturbation (FEP) simulations in the active and inactive conformations. The sequence and structure-based results are consistent and support the hypothesis that the inactive conformation DFG-out Activation Loop Folded, is a functional regulatory state that has been stabilized in TKs relative to STKs over the course of their evolution via the accumulation of residue substitutions in the activation loop and catalytic loop that facilitate distinct substrate binding modes in trans and additional modes of regulation in cis for TKs.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.