ArticleProtein science : a publication of the Protein Society2017
Germinal-center kinase-like kinase co-crystal structure reveals a swapped activation loop and C-terminal extension.
Article in Protein science : a publication of the Protein Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 22 citations in OpenAlex.
- From inhibition to degradation: advances in highly selective targeting strategies for HPK1.Molecular diversity · 2026Review
- A conserved dimerization element is required for protein kinase activation bybioRxiv : the preprint server for biology · 2026Article
- TNIK: A redox sensor in endothelial cell permeability.Science advances · 2024Article
- Functional annotation of the Hippo pathway somatic mutations in human cancers.Nature communications · 2024Article
- A critical evaluation of protein kinase regulation by activation loop autophosphorylation.eLife · 2023Article
- Synthesis and Evaluation of Novel 1,2,6-Thiadiazinone Kinase Inhibitors as Potent Inhibitors of Solid Tumors.Molecules (Basel, Switzerland) · 2021Article
- MAP4K3/GLK in autoimmune disease, cancer and aging.Journal of biomedical science · 2019Review
- Multiple conformational states of the HPK1 kinase domain in complex with sunitinib reveal the structural changes accompanying HPK1 trans-regulation.The Journal of biological chemistry · 2019Article
- Disordered Protein Kinase Regions in Regulation of Kinase Domain Cores.Trends in biochemical sciences · 2019Review
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Authors and funding
18 authors at 2 institutions in 1 country.
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Abstract
Germinal-center kinase-like kinase (GLK, Map4k3), a GCK-I family kinase, plays multiple roles in regulating apoptosis, amino acid sensing, and immune signaling. We describe here the crystal structure of an activation loop mutant of GLK kinase domain bound to an inhibitor. The structure reveals a weakly associated, activation-loop swapped dimer with more than 20 amino acids of ordered density at the carboxy-terminus. This C-terminal PEST region binds intermolecularly to the hydrophobic groove of the N-terminal domain of a neighboring molecule. Although the GLK activation loop mutant crystallized demonstrates reduced kinase activity, its structure demonstrates all the hallmarks of an "active" kinase, including the salt bridge between the C-helix glutamate and the catalytic lysine. Our compound displacement data suggests that the effect of the Ser170Ala mutation in reducing kinase activity is likely due to its effect in reducing substrate peptide binding affinity rather than reducing ATP binding or ATP turnover. This report details the first structure of GLK; comparison of its activation loop sequence and P-loop structure to that of Map4k4 suggests ideas for designing inhibitors that can distinguish between these family members to achieve selective pharmacological inhibitors.
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