Crystal structures of MKK4 kinase domain reveal that substrate peptide binds to an allosteric site and induces an auto-inhibition state.
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 p38α peptide (npMKK4/AMP/p38). These crystal structures revealed that the p38α 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 α-helix, which prevented substrate access to the active site and αC-helix movement to the active configuration of MKK4.
Matsumoto
Takashi
T
PharmAxess, Inc., 3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666, Japan.
Kinoshita
Takayoshi
T
Kirii
Yasuyuki
Y
Yokota
Koichi
K
Hamada
Kensaku
K
Tada
Toshiji
T
D000249:Adenosine Monophosphate / Q000737:chemistry; D000494:Allosteric Regulation; D000495:Allosteric Site; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry*
D010455:Peptides; D000249:Adenosine Monophosphate; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human