PDBsum entry 1h8f

Kinase

PDB id: 1h8f

Contents

Protein chain

352 a.a. *

Ligands

EPE ×2

Waters ×161

* Residue conservation analysis

PDB id:

1h8f

Name:

Kinase

Title:

Glycogen synthase kinase 3 beta.

Structure:

Glycogen synthase kinase-3 beta. Chain: a, b. Synonym: gsk3b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Biol. unit:

Dimer (from PQS)

Resolution:

2.80Å R-factor: 0.220 R-free: 0.256

Authors:

R.Dajani,L.H.Pearl,S.M.Roe

Key ref:

R.Dajani et al. (2001). Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell, 105, 721-732. PubMed id: 11440715 DOI: 10.1016/S0092-8674(01)00374-9

Date:

05-Feb-01 Release date: 31-Jan-02

Protein chains

P49841  (GSK3B_HUMAN) -  Glycogen synthase kinase-3 beta from Homo sapiens

Seq: 420 a.a.

Struc: 352 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Enzyme class 2: E.C.2.7.11.26 - [tau protein] kinase.
• Reaction:
  1. L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] + ADP + H⁺
  2. L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau protein] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/S0092-8674(01)00374-9

Cell 105:721-732 (2001)

PubMed id: 11440715

Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition.

R.Dajani, E.Fraser, S.M.Roe, N.Young, V.Good, T.C.Dale, L.H.Pearl.

ABSTRACT

Glycogen synthase kinase 3 beta (GSK3 beta) plays a key role in insulin and Wnt signaling, phosphorylating downstream targets by default, and becoming inhibited following the extracellular signaling event. The crystal structure of human GSK3 beta shows a catalytically active conformation in the absence of activation-segment phosphorylation, with the sulphonate of a buffer molecule bridging the activation-segment and N-terminal domain in the same way as the phosphate group of the activation-segment phospho-Ser/Thr in other kinases. The location of this oxyanion binding site in the substrate binding cleft indicates direct coupling of P+4 phosphate-primed substrate binding and catalytic activation, explains the ability of GSK3 beta to processively hyperphosphorylate substrates with Ser/Thr pentad-repeats, and suggests a mechanism for autoinhibition in which the phosphorylated N terminus binds as a competitive pseudosubstrate with phospho-Ser 9 occupying the P+4 site.

Selected figure(s)

Figure 1.
Figure 1. Structure of Human GSK3β(A) Stereo pair secondary structure cartoon of human glycogen synthase kinase 3β colored blue-red from the visible N terminus at residue 35 to the visible C terminus at residue 384. The orthogonal β barrel formed by the N-terminal domain is on the left. All molecular graphics were generated using Robert Esnouf's adaptation (Bobscript) of Molscript (Kraulis, 1991) and Raster3D (Merrit and Murphy, 1994), except for Figure 3 and Figure 6, which were generated with GRASP (Nicholls et al., 1993).(B) As (A), but with the view rotated by 90° around the horizontal

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

The above figures are reprinted by permission from Cell Press: Cell (2001, 105, 721-732) copyright 2001.

Figures were selected by an automated process.