PDBsum entry 5k5n

Transferase

PDB id: 5k5n

Contents

Protein chains

332 a.a.

Ligands

6QH ×2

SO4 ×2

Waters ×149

PDB id:

5k5n

Name:

Transferase

Title:

Crystal structure of gsk-3beta complexed with pf-04802367, a highly selective brain-penetrant kinase inhibitor

Structure:

Glycogen synthase kinase-3 beta. Chain: a, b. Fragment: residues 28-382. Synonym: gsk-3 beta,serine/threonine-protein kinase gsk3b. Engineered: yes. Mutation: yes

Source:

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

Resolution:

2.20Å R-factor: 0.205 R-free: 0.229

Authors:

R.G.Kurumbail,J.S.Chang

Key ref:

S.H.Liang et al. (2016). Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging. Angew Chem Int Ed Engl, 55, 9601-9605. PubMed id: 27355874 DOI: 10.1002/anie.201603797

Date:

23-May-16 Release date: 21-Sep-16

Protein chains

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

Seq: 420 a.a.

Struc: 332 a.a.

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: 10.1002/anie.201603797

Angew Chem Int Ed Engl 55:9601-9605 (2016)

PubMed id: 27355874

Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging.

S.H.Liang, J.M.Chen, M.D.Normandin, J.S.Chang, G.C.Chang, C.K.Taylor, P.Trapa, M.S.Plummer, K.S.Para, E.L.Conn, L.Lopresti-Morrow, L.F.Lanyon, J.M.Cook, K.E.Richter, C.E.Nolan, J.B.Schachter, F.Janat, Y.Che, V.Shanmugasundaram, B.A.Lefker, B.E.Enerson, E.Livni, L.Wang, N.J.Guehl, D.Patnaik, F.F.Wagner, R.Perlis, E.B.Holson, S.J.Haggarty, G.El Fakhri, R.G.Kurumbail, N.Vasdev.

ABSTRACT

Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A (11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.