6H0U

Glycogen synthase kinase-3 beta (GSK3) complex with a covalent [1,2,4]triazolo[1,5-a][1,3,5]triazine inhibitor

PDB DOI: https://doi.org/10.2210/pdb6H0U/pdb

Classification: TRANSFERASE
Organism(s): Homo sapiens
Expression System: Trichoplusia ni
Mutation(s): No

Deposited: 2018-07-10 Released: 2019-05-15
Deposition Author(s): Marcovich, I., Demitri, N., De Zorzi, R., Storici, P.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.30 ?
R-Value Free: 0.240
R-Value Work: 0.192
R-Value Observed: 0.195

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

A Triazolotriazine-Based Dual GSK-3 beta /CK-1 delta Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition.

Redenti, S., Marcovich, I., De Vita, T., Perez, C., De Zorzi, R., Demitri, N., Perez, D.I., Bottegoni, G., Bisignano, P., Bissaro, M., Moro, S., Martinez, A., Storici, P., Spalluto, G., Cavalli, A., Federico, S.

(2019) ChemMedChem 14: 310-314

PubMed: 30548443 Search on PubMed
DOI: https://doi.org/10.1002/cmdc.201800778
Primary Citation of Related Structures:
6H0U

PubMed Abstract:
Glycogen synthase kinase?3β (GSK-3β) and casein kinase?1δ (CK-1δ) are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking-based design. Compound 12, 3-(7-amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide, showed combined inhibitory activity against GSK-3β and CK-1δ [IC ₅₀ (GSK-3β)=0.17?μm; IC ₅₀ (CK-1δ)=0.68?μm]. In particular, classical ATP competition was observed against CK-1δ, and a co-crystal of compound 12 inside GSK-3β confirmed a covalent interaction between the cyanoacrylamide warhead and Cys199, which could help in the development of more potent covalent inhibitors of GSK-3β. Preliminary studies on in vitro models of Parkinson's disease revealed that compound 12 is not cytotoxic and shows neuroprotective activity. These results encourage further investigations to validate GSK-3β/CK-1δ inhibition as a possible new strategy to treat neuroinflammatory/degenerative diseases.

Organizational Affiliation

Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgeri 1, 34127, Trieste, Italy.

Macromolecule Content

Total Structure Weight: 94.73 kDa
Atom Count: 5,922
Modelled Residue Count: 696
Deposited Residue Count: 840
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Glycogen synthase kinase-3 beta	A, B	420	Homo sapiens	Mutation(s): 0 Gene Names: GSK3B EC: 2.7.11.26 (PDB Primary Data), 2.7.11.1 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P49841 (Homo sapiens) Explore P49841 Go to UniProtKB: P49841
PHAROS: P49841 GTEx: ENSG00000082701
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P49841
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
FKB (Subject of Investigation/LOI) Query on FKB Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain F [auth B] MOL2 format, chain C [auth A] MOL2 format, chain F [auth B] mmCIF format, chain C [auth A] mmCIF format, chain F [auth B]	C [auth A], F [auth B]	(2~{R})-3-[7-azanyl-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl]-2-cyano-propanamide C₁₄ H₁₉ N₉ O PQPBZNWOHODPRV-MRVPVSSYSA-N		Interactions Focus chain C [auth A] Focus chain F [auth B] Interactions & Density Focus chain C [auth A] Focus chain F [auth B]
MLI Query on MLI Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	MALONATE ION C₃ H₂ O₄ OFOBLEOULBTSOW-UHFFFAOYSA-L		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain G [auth B] SDF format, chain H [auth B] MOL2 format, chain E [auth A] MOL2 format, chain G [auth B] MOL2 format, chain H [auth B] mmCIF format, chain E [auth A] mmCIF format, chain G [auth B] mmCIF format, chain H [auth B]	E [auth A], G [auth B], H [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain G [auth B] Focus chain H [auth B] Interactions & Density Focus chain E [auth A] Focus chain G [auth B] Focus chain H [auth B]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain I [auth B] SDF format, chain J [auth B] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] mmCIF format, chain I [auth B] mmCIF format, chain J [auth B]	I [auth B], J [auth B]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain I [auth B] Focus chain J [auth B] Interactions & Density Focus chain I [auth B] Focus chain J [auth B]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain K [auth B] MOL2 format, chain K [auth B] mmCIF format, chain K [auth B]	K [auth B]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain K [auth B] Interactions & Density Focus chain K [auth B]