Investigating Inactive Conformations of Protein Kinases

Abstract

Protein kinases comprise a substantial fraction of the human genome and constitute a wide array of cell signaling pathways that control countless cellular processes. Improper kinase regulation has been implicated in a number of grievous diseases; hence, these enzymes have become prominent therapeutic targets. The crux of kinase regulation lies in the ability of these proteins to switch between catalytically active and inactive conformations. The latter have recently gained prominence as drug targets in an effort to achieve selectivity in a family of more than 500 members with very similar active sites. However, despite the pharmacological significance of inactive conformations, neither their biophysical properties nor their potential roles in kinase regulation have been thoroughly investigated. The first two chapters of this work explore the determinants of a specific inactive kinase conformation, its potential physiological consequences, and how it can be used to study noncatalytic kinase functions. The final chapter examines how kinase inhibitor potency is affected by specific architectural motifs within kinases. It is expected that insight gained from this work will aid kinase drug development and enhance our knowledge of kinase regulation.