5nzz

Crystal structure of phosphorylated p38aMAPK in complex with TAB1

spinqualitylabelsall models 5nzz, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5nzz is a 8 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: AGS, MG, NI, PTR, TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TAB1_HUMAN May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis. Publication Abstract from PubMed Inhibiting MAPK14 (p38alpha) diminishes cardiac damage in myocardial ischemia. During myocardial ischemia, p38alpha interacts with TAB1, a scaffold protein, which promotes p38alpha autoactivation; active p38alpha (pp38alpha) then transphosphorylates TAB1. Previously, we solved the X-ray structure of the p38alpha-TAB1 (residues 384-412) complex. Here, we further characterize the interaction by solving the structure of the pp38alpha-TAB1 (residues 1-438) complex in the active state. Based on this information, we created a global knock-in (KI) mouse with substitution of 4 residues on TAB1 that we show are required for docking onto p38alpha. Whereas ablating p38alpha or TAB1 resulted in early embryonal lethality, the TAB1-KI mice were viable and had no appreciable alteration in their lymphocyte repertoire or myocardial transcriptional profile; nonetheless, following in vivo regional myocardial ischemia, infarction volume was significantly reduced and the transphosphorylation of TAB1 was disabled. Unexpectedly, the activation of myocardial p38alpha during ischemia was only mildly attenuated in TAB1-KI hearts. We also identified a group of fragments able to disrupt the interaction between p38alpha and TAB1. We conclude that the interaction between the 2 proteins can be targeted with small molecules. The data reveal that it is possible to selectively inhibit signaling downstream of p38alpha to attenuate ischemic injury. The TAB1-p38alpha complex aggravates myocardial injury and can be targeted by small molecules.,De Nicola GF, Bassi R, Nichols C, Fernandez-Caggiano M, Golforoush PA, Thapa D, Anderson R, Martin ED, Verma S, Kleinjung J, Laing A, Hutchinson JP, Eaton P, Clark J, Marber MS JCI Insight. 2018 Aug 23;3(16). pii: 121144. doi: 10.1172/jci.insight.121144. PMID:30135318 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Mitogen-activated protein kinase 3D structures

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