PDBsum entry 5f95

Transferase/transferase inhibitor

PDB id: 5f95

Contents

Protein chains

345 a.a.

Ligands

3UP ×2

Waters ×69

PDB id:

5f95

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of gsk3b in complex with compound 18: 2- [(cyclopropylcarbonyl)amino]-n-(4-phenylpyridin-3-yl)pyridine-4- carboxamide

Structure:

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: gsk3b. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469

Resolution:

2.53Å R-factor: 0.204 R-free: 0.242

Authors:

H.A.Lewis,K.Kish,G.Luo,G.M.Dubowchick

Key ref:

G.Luo et al. (2016). Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors. J Med Chem, 59, 1041-1051. PubMed id: 26751161 DOI: 10.1021/acs.jmedchem.5b01550

Date:

09-Dec-15 Release date: 03-Feb-16

Protein chains

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

Seq: 420 a.a.

Struc: 345 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: 10.1021/acs.jmedchem.5b01550

J Med Chem 59:1041-1051 (2016)

PubMed id: 26751161

Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors.

G.Luo, L.Chen, C.R.Burton, H.Xiao, P.Sivaprakasam, C.M.Krause, Y.Cao, N.Liu, J.Lippy, W.J.Clarke, K.Snow, J.Raybon, V.Arora, M.Pokross, K.Kish, H.A.Lewis, D.R.Langley, J.E.Macor, G.M.Dubowchik.

ABSTRACT

GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.