The ErbB family of receptor tyrosine kinases, which includes EGFR (HER1), HER2, HER3, and HER4, is an important target of small-molecule kinase inhibitors in the treatment of human cancers.  However, point mutations in cancer cells have led to the emergence of resistance to these drugs and have most recently been shown to be mediated by HER3.  Efforts to inhibit HER3 have proven to be difficult because it is believed to be catalytically inactive (a 'pseudokinase') due to amino acid substitutions in the conserved kinase domain.  Specifically, it lacks a catalytic base aspartate, which deters from phosphorylating protein substrates.  Thus there is a growing interest in characterizing the molecular features of HER3 that, despite seeming to lack catalytic activity, enable it to mediate drug resistance.  Here we construct a model of the ternary complex of HER3 kinase bound to ATP and a tyrosine-containing substrate peptide, based on a HER3 crystal structure that has recently been solved in collaborative experiments with the Mark Lemmon lab at UPenn [Shi F. et al. 2010. PNAS].  We compare the possible catalytic mechanisms in EGFR and HER3 through free energy calculations and mixed quantum mechanics molecular mechanics (QM/MM) simulations.  Our QM/MM simulations reveal that phosphotransfer in HER3 may proceed along an alternate pathway which does not require the conserved catalytic aspartate.  Based on the QM/MM activation energies, the HER3 pathway is much slower than EGFR, which correlates with the low level of autocatalytic activity observed in our collaborative experiments.  Thus HER3 may represent a novel therapeutic target of small-molecule kinase inhibitors.

Molecular modeling and simulation of the HER3/ErbB3 pseudo-kinase domain

240th National Meeting (2010)

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