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Crystal structures of MKK4 kinase domain reveal that substrate peptide binds to an allosteric site and induces an auto-inhibition state |
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| Authors: | Takashi Matsumoto Takayoshi Kinoshita Koichi Yokota Toshiji Tada |
| Affiliation: | a PharmAxess, Inc., 3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666, Japan b Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka 599-8531, Japan c Carna Biosciences, Inc., BMA 3F, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan |
| Abstract: | 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. |
| Keywords: | JNK, c-Jun NH2-terminal kinase MAP, mitogen-activated protein MKK, MAP kinase kinase MKKK, MAP kinase kinase kinase IPTG, isopropyl-β-d-thiogalactopyranoside npMKK4, non-phosphorylated MKK4 kinase domain AMP-PNP, adenylyl-imidodiphosphate rmsd, root-mean-square deviation ATP, adenosine triphosphate |
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