Significance Signaling pathways often use kinase cascades, but structural characterization of catalytic complexes between heterodimeric kinase pairs has been elusive. For MAPK–MAPKAPK binary complexes, a high-affinity “docking” interaction holds kinase domains proximal within a tethered complex. This heterodimer provided a unique opportunity to shed light on kinase domain–domain contacts that play a role in the assembly of the transient catalytic complex. Starting out from a new precatalytic extracellular signal regulated kinase 2–ribosomal S6 kinase 1 (ERK2–RSK1) crystallographic complex, where the activation loop of the downstream kinase (RSK1) faced the enzyme's (ERK2) catalytic site, we used molecular dynamics simulation to show how the catalytic ERK2–RSK1 complex forms. Our findings reveal the dynamic process through which transient, physiologically relevant kinase heterodimers form in a prototypical kinase cascade.