Computational Models for Activated Human MEK1: Identification of Key Active Site Residues and Interactions

MEK1 is a protein
kinase in the MAPK cellular signaling pathway
that is notable for its dual specificity and its potential as a drug
target for a variety of cancer therapies. While much is known about
the key role of MEK1 in signaling events, understanding of the structural
features that sustain MEK1 function remains limited because of the
absence of crystal or NMR structural insights into the phosphorylated
and activated form of MEK1. In this work, homology modeling was used
to overcome this limitation and generate computational models of the
doubly phosphorylated active MEK1 conformation. A variety of models
were generated using crystal structures of active protein kinases
as homology model templates. These models were equilibrated using
molecular dynamics simulations, and each model was validated against
several known structural characteristics of activated kinases. The
best model structures were used in docking studies with ATP and a
small peptide sequence that represents the activation loop of ERK2
to identify the most important residues in stabilizing protein docking
and phosphorylation. These results provide insights for the pursuit
of structure-guided mutagenesis and drug design.