4l43

Crystal structures of human p70S6K1-T389A (form I)

spinqualitylabelsall models 4l43, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4l43 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 5FI Related: 4l3j, 4l3l, 4l42, 4l44, 4l45, 4l46 Gene: RPS6KB1, hCG_1815774 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The activity of the ribosome protein subunit 6 kinase 1 (S6K1) is stimulated by phosphorylation of Thr389 in the hydrophobic motif by mTORC1 and phosphorylation of Thr229 in the activation loop by PDK1; however, the order of the two events is still ambiguous. Here we report six crystal structures of the S6K1 kinase domain alone or plus the hydrophobic motif in various forms, in complexes with a highly specific inhibitor. The structural data together with the biochemical data reveal in vivo phosphorylation of Thr389 in the absence of Thr229 phosphorylation and demonstrate the importance of two conserved residues, Gln140 and Arg121, in the establishment of a hydrogen-bonding network between the N-lobe and the hydrophobic motif. Phosphorylation of Thr389 or introduction of a corresponding negatively charged group leads to reinforcement of the network and stabilization of helix alphaC. Furthermore, comparisons of S6K1 with other AGC family kinases suggest that the structural and sequence differences in the hydrophobic motif and helix alphaC account for their divergence in PDK1 dependency. Together, these results indicate that phosphorylation of the hydrophobic motif in S6K1 is independent of and probably, precedes and promotes phosphorylation of the activation loop. Crystal structures of S6K1 provide insights into the regulation mechanism of S6K1 by the hydrophobic motif.,Wang J, Zhong C, Wang F, Qu F, Ding J Biochem J. 2013 Jun 3. PMID:23731517 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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