PDBsum entry 3zdi

Transferase/peptide

PDB id: 3zdi

Contents

Protein chains

349 a.a.

17 a.a.

Ligands

PO4

UGJ

Waters ×70

PDB id:

3zdi

Name:

Transferase/peptide

Title:

Glycogen synthase kinase 3 beta complexed with axin peptide and inhibitor 7d

Structure:

Glycogen synthase kinase-3 beta. Chain: a. Fragment: residues 35-384. Synonym: gsk-3 beta, serine/threonine-protein kinase gsk3b. Engineered: yes. Other_details: phosphotyrosine at a216. Axin-1. Chain: b. Fragment: residues 383-400.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Synthetic: yes. Organism_taxid: 9606

Resolution:

2.65Å R-factor: 0.204 R-free: 0.242

Authors:

A.E.Oberholzer,L.H.Pearl

Key ref:

W.Fugel et al. (2013). 3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are selective inhibitors of Plasmodium falciparum glycogen synthase kinase-3. J Med Chem, 56, 264-275. PubMed id: 23214499

Date:

27-Nov-12 Release date: 26-Dec-12

Protein chain

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

Seq: 420 a.a.

Struc: 349 a.a.

Protein chain

O15169  (AXIN1_HUMAN) -  Axin-1 from Homo sapiens

Seq: 862 a.a.

Struc: 17 a.a.

Enzyme reactions

• Enzyme class 1: Chain A: 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: Chain A: 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

J Med Chem 56:264-275 (2013)

PubMed id: 23214499

3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are selective inhibitors of Plasmodium falciparum glycogen synthase kinase-3.

W.Fugel, A.E.Oberholzer, B.Gschloessl, R.Dzikowski, N.Pressburger, L.Preu, L.H.Pearl, B.Baratte, M.Ratin, I.Okun, C.Doerig, S.Kruggel, T.Lemcke, L.Meijer, C.Kunick.

ABSTRACT

Plasmodium falciparum is the infective agent responsible for malaria tropica. The glycogen synthase kinase-3 of the parasite (PfGSK-3) was suggested as a potential biological target for novel antimalarial drugs. Starting from hit structures identified in a high-throughput screening campaign, 3,6-diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles were discovered as a new class of PfGSK-3 inhibitors. Being less active on GSK-3 homologues of other species, the title compounds showed selectivity in favor of PfGSK-3. Taking into account the X-ray structure of a related molecule in complex with human GSK-3 (HsGSK-3), a model was computed for the comparison of inhibitor complexes with the plasmodial and human enzymes. It was found that subtle differences in the ATP-binding pockets are responsible for the observed PfGSK-3 vs HsGSK-3 selectivity. Representatives of the title compound class exhibited micromolar IC(50) values against P. falciparum erythrocyte stage parasites. These results suggest that inhibitors of PfGSK-3 could be developed as potential antimalarial drugs.