PDBsum entry 5hlp

Transferase/transferase inhibitor

PDB id: 5hlp

Contents

Protein chains

339 a.a.

Ligands

65A ×2

Waters ×104

PDB id:

5hlp

Name:

Transferase/transferase inhibitor

Title:

X-ray crystal structure of gsk3b in complex with brd3937

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: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.45Å R-factor: 0.190 R-free: 0.240

Authors:

A.White,D.Lakshminarasimhan,A.Nadupalli,R.K.Suto

Key ref:

F.F.Wagner et al. (2016). Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects. Acs Chem Biol, 11, 1952-1963. PubMed id: 27128528 DOI: 10.1021/acschembio.6b00306

Date:

15-Jan-16 Release date: 25-May-16

Protein chains

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

Seq: 420 a.a.

Struc: 339 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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/acschembio.6b00306

Acs Chem Biol 11:1952-1963 (2016)

PubMed id: 27128528

Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects.

F.F.Wagner, J.A.Bishop, J.P.Gale, X.Shi, M.Walk, J.Ketterman, D.Patnaik, D.Barker, D.Walpita, A.J.Campbell, S.Nguyen, M.Lewis, L.Ross, M.Weïwer, W.F.An, A.R.Germain, P.P.Nag, S.Metkar, T.Kaya, S.Dandapani, D.E.Olson, A.L.Barbe, F.Lazzaro, J.R.Sacher, J.H.Cheah, D.Fei, J.Perez, B.Munoz, M.Palmer, K.Stegmaier, S.L.Schreiber, E.Scolnick, Y.L.Zhang, S.J.Haggarty, E.B.Holson, J.Q.Pan.

ABSTRACT

The mood stabilizer lithium, the first-line treatment for bipolar disorder, is hypothesized to exert its effects through direct inhibition of glycogen synthase kinase 3 (GSK3) and indirectly by increasing GSK3's inhibitory serine phosphorylation. GSK3 comprises two highly similar paralogs, GSK3α and GSK3β, which are key regulatory kinases in the canonical Wnt pathway. GSK3 stands as a nodal target within this pathway and is an attractive therapeutic target for multiple indications. Despite being an active field of research for the past 20 years, many GSK3 inhibitors demonstrate either poor to moderate selectivity versus the broader human kinome or physicochemical properties unsuitable for use in in vitro systems or in vivo models. A nonconventional analysis of data from a GSK3β inhibitor high-throughput screening campaign, which excluded known GSK3 inhibitor chemotypes, led to the discovery of a novel pyrazolo-tetrahydroquinolinone scaffold with unparalleled kinome-wide selectivity for the GSK3 kinases. Taking advantage of an uncommon tridentate interaction with the hinge region of GSK3, we developed highly selective and potent GSK3 inhibitors, BRD1652 and BRD0209, which demonstrated in vivo efficacy in a dopaminergic signaling paradigm modeling mood-related disorders. These new chemical probes open the way for exclusive analyses of the function of GSK3 kinases in multiple signaling pathways involved in many prevalent disorders.