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Title: Structure Prediction and Validation of the ERK8 Kinase Domain
Authors: Strambi, A.
Mori, Mattia 
Rossi, M.
Colecchia, D.
Manetti, Fabrizio 
Carlomagno, F.
Botta, Maurizio 
Chiariello, M.
Issue Date: 2013
Project: None 
Journal: PLOS ONE
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.
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0052011
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