Dynamic conformational states of apo, ATP and cabozantinib bound TAM kinases to differentiate active-inactive kinetic...

The dynamically active and inactive conformations of kinases play a crucial role in the activation of intracellular downstream signaling pathways. The all-atom molecular dynamics (MD) simulations at microsecond (µs) timescale and longer provide robust insights into the structural details of conformational alterations in kinases that contribute to their cellular metabolic activities and signaling pathways. Tyro3, Axl and Mer (TAM) receptor tyrosine kinases (RTKs) are overexpressed in several types of human cancers. Cabozantinib, a small molecule inhibitor constrains the activity of TAM kinases at nanomolar concentrations. The apo, complexes of ATP (active state) and cabozantinib (active and inactive states) with TAM RTKs were studied by 1 µs MD simulations followed by trajectory analyses. The dynamic mechanistic pathways intrinsic to the kinase activity and protein conformational landscape in the cabozantinib bound TAM kinases are revealed due to the alterations in the P-loop, α-helix and activation loop that result in breaking the regulatory (R) and catalytic (C) spines, while the active states of ATP bound TAM kinases are retained. The co-existence of dynamical states when bound to cabozantinib was observed and the long-lived kinetic transition states of distinct active and inactive structural models were deciphered from MD simulation trajectories that have not been revealed so far.Communicated by Ramaswamy H. Sarma.