ABSTRACT: ErbB4, a receptor tyrosine kinase of the ErbB family, plays
crucial roles in cell growth and differentiation, especially in the
development of the heart and nervous system. Ligand binding to its
extracellular region could modulate the activation process. To understand
the mechanism of ErbB4 activation induced by ligand binding, we
performed one microsecond molecular dynamics (MD) simulations on
the ErbB4 extracellular region (ECR) with and without its endogenous
ligand neuregulin1β (NRG1β). The conformational transition of the
ECR-ErbB4/NRG1β complex from a tethered inactive conformation to
an extended active-like form has been observed, while such large and
function-related conformational change has not been seen in the
simulation on the ECR-ErbB4, suggesting that ligand binding is indeed
the active inducing force for the conformational transition and further dimerization. On the basis of MD simulations and
principal component analysis, we constructed a rough energy landscape for the conformational transition of ECR-ErbB4/NRG1β
complex, suggesting that the conformational change from the inactive state to active-like state involves a stable conformation.
The energy barrier for the tether opening was estimated as ∼2.7 kcal/mol, which is very close to the experimental value (1−2
kcal/mol) reported for ErbB1. On the basis of the simulation results, an atomic mechanism for the ligand-induced activation of
ErbB4 was postulated. The present MD simulations provide a new insight into the conformational changes underlying the
activation of ErbB4.