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Structure prediction and validation of the ERK8 kinase domain.

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 structure-based 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.

SUBMITTER: Strambi A

PROVIDER: S-EPMC3543423 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Structure prediction and validation of the ERK8 kinase domain.

Strambi Angela A Mori Mattia M Rossi Matteo M Colecchia David D Manetti Fabrizio F Carlomagno Francesca F Botta Maurizio M Chiariello Mario M

PloS one 20130111 1

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 structure-based virtual screening protocol consisting of pharmacophore screening and molecular docking. Experimental characterization of the hit c ...[more]

PMID: 23326322

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