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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Matsumoto T, Kinoshita T, Kirii Y, Yokota K, Hamada K, Tada T
Crystal structures of MKK4 kinase domain reveal that substrate peptide binds to an allosteric site and induces an auto-inhibition state.
Biochem Biophys Res Commun. 2010 Sep 24;400(3):369-73. doi: 10.1016/j.bbrc.2010.08.071. Epub 2010 Aug 21.
- PubMed ID
- 20732303 [ View in PubMed]
- 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 p38alpha peptide (npMKK4/AMP/p38). These crystal structures revealed that the p38alpha 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 alphaC-helix movement to the active configuration of MKK4.