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 neuregulin1 beta (NRG1 beta). The conformational transition of the ECR-ErbB4/NRG1 beta 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/NRG1 beta 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 similar to 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.