PDBsum entry 1q4l

Transferase

PDB id: 1q4l

Contents

Protein chain

342 a.a. *

Ligands

679 ×2

Waters ×47

* Residue conservation analysis

PDB id:

1q4l

Name:

Transferase

Title:

Gsk-3 beta complexed with inhibitor i-5

Structure:

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: gsk3b. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: h5.

Resolution:

2.77Å R-factor: 0.212 R-free: 0.251

Authors:

J.A.Bertrand,S.Thieffine,A.Vulpetti,C.Cristiani,B.Valsasina,S.Knapp, H.M.Kalisz,M.Flocco

Key ref:

J.A.Bertrand et al. (2003). Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors. J Mol Biol, 333, 393-407. PubMed id: 14529625 DOI: 10.1016/j.jmb.2003.08.031

Date:

04-Aug-03 Release date: 14-Oct-03

Protein chains

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

Seq: 420 a.a.

Struc: 342 a.a.

Enzyme reactions

• Enzyme class: 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⁺

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

reference

DOI no: 10.1016/j.jmb.2003.08.031

J Mol Biol 333:393-407 (2003)

PubMed id: 14529625

Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors.

J.A.Bertrand, S.Thieffine, A.Vulpetti, C.Cristiani, B.Valsasina, S.Knapp, H.M.Kalisz, M.Flocco.

ABSTRACT

GSK-3beta is a regulatory serine/threonine kinase with a plethora of cellular targets. Consequently, selective small molecule inhibitors of GSK-3beta may have a variety of therapeutic uses including the treatment of neurodegenerative diseases, type II diabetes and cancer. In order to characterize the active site of GSK-3beta, we determined crystal structures of unphosphorylated GSK-3beta in complex with selective and non-selective ATP-mimetic inhibitors. Analysis of the inhibitors' interactions with GSK-3beta in the structures reveals how the enzyme can accommodate a number of diverse molecular scaffolds. In addition, a conserved water molecule near Thr138 is identified that can serve a functional role in inhibitor binding. Finally, a comparison of the interactions made by selective and non-selective inhibitors highlights residues on the edge of the ATP binding-site that can be used to obtain inhibitor selectivity. Information gained from these structures provides a promising route for the design of second-generation GSK-3beta inhibitors.

Selected figure(s)

Figure 4.
Figure 4. Diagram showing the binding of (a) AMP-PNP, (b) staurosporine, (c) indirubin-3-monoxime and (d) alsterpaullone to GSK-3b. Residues playing a direct or indirect role in inhibitor binding are shown in a ball-and-stick representation. Inhibitor molecules are shown in tan; water molecules and Mg2+ are shown in red and yellow, respectively. The C^a trace of GSK-3b is shown in blue and green for the N- and C-terminal domains, respectively. To avoid "cluttering" in the AMP-PNP diagram, the two water molecules coordinating Mg1 are omitted and Asp200, the residue coordinating Mg1 and Mg2, is unlabelled.

Figure 6.
Figure 6. Stereo view showing I-5 bound in the GSK-3b active site. Residues playing a direct or indirect role in inhibitor binding are shown in a ball-and-stick representation. I-5 is shown in light brown; chlorine atoms are in green and water molecules are in red. The C^a trace of GSK-3b is shown in blue and green for the N- and C-terminal domains, respectively. For the sake of clarity, Leu132 and Tyr134 are unlabelled and Val110 has been omitted from the Figure.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2003, 333, 393-407) copyright 2003.

Figures were selected by an automated process.