Kinases are molecular switches that control specific intracellular pathways and interactions with high fidelity making them attractive therapeutic targets for a range of indications, including neurological and psychiatric disorders. There are 518 kinases found within the human kinome which account for approximately 2% of all human genes. Kinases share common structural motifs and specifically recognize, bind and use ATP to transfer a phosphate group to substrates. Therefore making specific competitive inhibitors, although attractive from a therapeutic standpoint, proves extremely difficult in practice. Molecular modeling is used in this work to help understand in atomic detail how GSK3α and GSK3β, two paralogs with 100% sequence similarity in the ATP binding pocket, are structurally and functionally different. We show how a single amino acid difference, a D/E switch, on the hinge of these kinases drives these differences. We apply these learning’s more broadly to show that the D/E switch is not unique and found across the larger human kinome.

Structural implications of hinge D/E switching in the human kinome

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.