Abstract 2232: Computational modeling reveals druggable cavities at the MKK3 and p38 protein interaction interface.
Andrei A. Ivanov, Satra Nim, Yuhong Du, Haian Fu · Cancer Research · 2013
Abstract Mitogen-activated protein kinase (MAPK) cascades play vital roles in transmitting regulatory signals that control diverse physiological processes. Among them, MAPK p38 is critical for immune response, cell survival, and differentiation. The importance of the MKK3-p38 pathway in the development of cancer, asthma, inflammatory and other diseases is well-established. Accordingly, many inhibitors of p38 have been developed, some of which have entered clinical trials. Our research indicates that the MKK3-p38 interaction, upstream of p38 itself, forms a critical node in a network of protein-protein interactions (PPI) important for cell growth. Thus, pathway blockers that target the MKK3-p38 PPI interface may have therapeutic potential beyond p38 kinase inhibitors. To discover MKK3-p38 PPI inhibitors, we took an experimentally-based computational approach, which led to the identification of a PPI interface and molecular tools for therapeutic interrogation. Our biological studies revealed a short inhibitory peptide located at the N-terminus of p38, which effectively disrupts the MKK3-p38 interaction in vitro and in vivo via its binding to MKK3. In this study, the structural organization of MKK3-p38 complex and the molecular mechanisms of peptide binding were investigated with computational modeling methods. We constructed the first model of MKK3, its complex with MAPK p38, and binding of the short inhibitory peptide to the MKK3 surface. Using this model, we have proposed several potentially druggable cavities on the molecular surfaces of both the MKK3 and p38 kinases. We found that the p38 N-terminal peptide can occupy the same cavity on the MKK3 surface as the p38 phosphorylation loop. Further, we have proposed the peptide residues playing the most important role in MKK3 binding. Overall, our data provide a basis for the rational design and screening for small molecule inhibitors of the MKK3-p38 interaction as regulators of the p38 signaling pathway. Citation Format: Andrei A. Ivanov, Satra Nim, Yuhong Du, Haian Fu. Computational modeling reveals druggable cavities at the MKK3 and p38 protein interaction interface. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2232. doi:10.1158/1538-7445.AM2013-2232