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Figure 4.
Figure 4. Phospho-Substrate Binding Model and Tyr 216
Conformation(A) Model of substrate binding to GSK3β based on
structural alignment with the structure of a phosphorylase
kinase–peptide substrate complex (PDB code 2PHK). The modeled
substrate corresponds to residues 642–648 of human glycogen
synthase (-642-PPSPSLS-648), whose phosphorylation at Ser 644 by
GSK3β requires a “priming” phosphoserine at 648. The
position of the serine to be phosphorylated is indicated at P(0)
and that of the priming phospho-serine at P(+4). The phosphate
at P(+4) occupies the same position as the sulphonate of the
bound HEPES. The rotamer of Tyr 216 was changed to an anti
conformation to eliminate steric clashes.(B) Comparison of the
conformations of the activation segment tyrosine in GSK3β
(left) and the phosphorylated equivalent tyrosine in activated
ERK2. Simple rotation of the side chain of Tyr 216 in GSK3β
around the Cα-Cβ bond brings it into the same position as the
pTyr 185 in ERK2, and, if phosphorylated, would be stabilized in
that conformation by interaction with Arg 220 and Arg 223
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