Mitogen-activated protein kinase (MAPK) p38 pathway plays a critical role in immune response, cell survival, and differentiation. Mounting evidence supports a critical role of the MKK3-p38 pathway in the development of cancer, asthma, inflammatory and other diseases. Accordingly, many inhibitors of p38 have been developed, some of which have entered clinical trials.  However, pathway inhibitors that target the MKK3-p38 protein-protein interaction (PPI) interface have not been reported. As the first step in design of this novel type of MAPK pathway modulating compounds, we have constructed a computational model of the MKK3-p38 complex using homology modeling and protein-protein docking approaches. The model led to identification of amino acid residues of MKK3 and p38 critical for protein-protein binding. The results of molecular modeling were found in an agreement with our biological studies. Our model is expected to guide the development of the MKK3/p38 PPI inhibitors.

Computational modeling of the MKK3-p38 interaction interface

243rd National Meeting (2012)

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