Extracellular signal-regulated kinase 8 (ERK8) has been already implicated in cell transformation and in the protection of genomic integrity and, therefore, proposed as a novel potential therapeutic target for cancer. In the absence of a crystal structure, we developed a three-dimensional model for its kinase domain. To validate our model we applied a structurebased virtual screening protocol consisting of pharmacophore screening and molecular docking. Experimental characterization of the hit compounds confirmed that a high percentage of the identified scaffolds was able to inhibit ERK8. We also confirmed an ATP competitive mechanism of action for the two best-performing molecules. Ultimately, we identified an ERK8 drug-resistant ‘‘gatekeeper’’ mutant that corroborated the predicted molecular binding mode, confirming the reliability of the generated structure. We expect that our model will be a valuable tool for the development of specific ERK8 kinase inhibitors.

Strambi, A., Mori, M., Rossi, M., Colecchia, D., Manetti, F., Carlomagno, F., et al. (2013). Structure Prediction and Validation of the ERK8 Kinase Domain. PLOS ONE, 8, e52011-1-e52011-14 [10.1371/journal.pone.0052011].

Structure Prediction and Validation of the ERK8 Kinase Domain

MORI, MATTIA;MANETTI, FABRIZIO;BOTTA, MAURIZIO;
2013

Abstract

Extracellular signal-regulated kinase 8 (ERK8) has been already implicated in cell transformation and in the protection of genomic integrity and, therefore, proposed as a novel potential therapeutic target for cancer. In the absence of a crystal structure, we developed a three-dimensional model for its kinase domain. To validate our model we applied a structurebased virtual screening protocol consisting of pharmacophore screening and molecular docking. Experimental characterization of the hit compounds confirmed that a high percentage of the identified scaffolds was able to inhibit ERK8. We also confirmed an ATP competitive mechanism of action for the two best-performing molecules. Ultimately, we identified an ERK8 drug-resistant ‘‘gatekeeper’’ mutant that corroborated the predicted molecular binding mode, confirming the reliability of the generated structure. We expect that our model will be a valuable tool for the development of specific ERK8 kinase inhibitors.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11365/43756
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