Inter-lobe Motions Allosterically Regulate the Structure and Function of EGFR Kinase.

Abstract Protein kinases play important roles in cellular signaling and have been one of the best studied drug targets. The kinase domain of epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that has been extensively studied for cancer drug discovery and for understanding the unique activation mechanism by dimerization. Here, we analyzed all available 206 crystal structures of the EGFR kinase and the dynamics observed in molecular simulations to identify how these structures are determined. It was found that the arrangement between the N- and C-terminal lobes plays a key role in regulating the kinase structure by sensitively responding to the intermolecular interactions, or the crystal environment. A whole variety of crystal forms in the database is thus reflected in the broad distribution of the inter-lobe arrangement. The configuration of the catalytically important motifs as well as the bound ATP is closely coupled with the inter-lobe motion. When the intermolecular interactions are those of the activating asymmetric dimer, EGFR kinase takes the open-lobe arrangement that constructs the catalytically active configuration.