MKK4 activates both JNKs and p38s We determined the crystal structures of human non-phosphorylated MKK4 kinase domain (npMKK4) complexed with AMP-PNP (npMKK4/AMP) and a ternary complex of npMKK4. AMP-PNP and p38 alpha peptide (npMKK4/AMP/p38) These crystal structures revealed that the p38 alpha peptide-bound npMKK4 at the allosteric site rather than at the putative substrate binding site and induced an auto-inhibition state. While the activation loop of the npMKK4/AMP complex was disordered. in the npMKK4/AMP/p38 complex it configured a long alpha-helix, which prevented substrate access to the active site and alpha C-helix movement to the active configuration of MKK4. (C) 2010 Elsevier Inc All rights reserved