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Matsumoto T.,PharmAxess Inc. | Matsumoto T.,Osaka Prefecture University | Matsumoto T.,Rigaku Corporation. | Kinoshita T.,Osaka Prefecture University | And 6 more authors.
Journal of Biochemistry | Year: 2012

Mitogen-activated protein kinase kinase 6 (MAP2K6) plays a crucial role in the p38 MAP kinase signal cascade that regulates various stress-induced responses and is associated with pathological conditions. The crystal structure of human non-phosphorylated MAP2K6 (npMAP2K6) complexed with an ATP analogue was determined at 2.6 resolution and represents an auto-inhibition state of MAP2K6. Three characteristics of short α-helices configured in the activation loop region, termed activation helices (AH1, AH2 and AH3), are important in controlling the auto-inhibition mechanism. AH1 displaces the αC-helix, a component essential for forming the active configuration, away from the active site. AH1 and AH2 were found to enclose the γ-phosphate, the leaving group of ATP. A comparison with the related enzymes, MAP2K1 and MAP2K4 reveals that MAP2K6 has the unique auto-inhibition mechanism mediated by the three activation helices. © 2012 The Authors.


Matsumoto T.,PharmAxess Inc. | Matsumoto T.,Osaka Prefecture University | Kinoshita T.,Osaka Prefecture University | Kirii Y.,Carna Biosciences Inc. | And 3 more authors.
Biochemical and Biophysical Research Communications | Year: 2010

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. © 2010 Elsevier Inc.


Morioka H.,Osaka University of Pharmaceutical Sciences | Miki Y.,Osaka University of Pharmaceutical Sciences | Saito K.,Osaka University of Pharmaceutical Sciences | Tomoo K.,Osaka University of Pharmaceutical Sciences | And 6 more authors.
Acta Crystallographica Section F: Structural Biology and Crystallization Communications | Year: 2010

BxlA from Streptomyces thermoviolaceus OPC-520, together with the extra-cellular BxlE and the integral membrane proteins BxlF and BxlG, constitutes a xylanolytic system that participates in the intracellular transport of xylan-degradation products and the production of xylose. To elucidate the mechanism of the hydrolytic degradation of xylooligosaccharides to xylose at the atomic level, X - ray structural analysis of BxlA was attempted. The recombinant BxlA protein (molecular weight 82 kDa) was crystallized by the hanging-drop vapour-diffusion method at 289 K. The crystals belonged to the monoclinic space group C2, with unit-cell parameters a = 142.2, b = 129.5, c = 101.4 Å, β = 119.8°, and contained two molecules per asymmetric unit (VM = 2.47 Å3 Da-1). Diffraction data were collected to a resolution to 2.50 Å and provided a data set with an overall Rmerge of 8.3%. © 2010 International Union of Crystallography. All rights reserved.


PubMed | PharmAxess Inc.
Type: Journal Article | Journal: Biochemical and biophysical research communications | Year: 2010

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 peptide (npMKK4/AMP/p38). These crystal structures revealed that the p38 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 -helix, which prevented substrate access to the active site and C-helix movement to the active configuration of MKK4.


PubMed | PharmAxess Inc.
Type: Journal Article | Journal: Journal of biochemistry | Year: 2012

Mitogen-activated protein kinase kinase 6 (MAP2K6) plays a crucial role in the p38 MAP kinase signal cascade that regulates various stress-induced responses and is associated with pathological conditions. The crystal structure of human non-phosphorylated MAP2K6 (npMAP2K6) complexed with an ATP analogue was determined at 2.6 resolution and represents an auto-inhibition state of MAP2K6. Three characteristics of short -helices configured in the activation loop region, termed activation helices (AH1, AH2 and AH3), are important in controlling the auto-inhibition mechanism. AH1 displaces the C-helix, a component essential for forming the active configuration, away from the active site. AH1 and AH2 were found to enclose the -phosphate, the leaving group of ATP. A comparison with the related enzymes, MAP2K1 and MAP2K4 reveals that MAP2K6 has the unique auto-inhibition mechanism mediated by the three activation helices.

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