Evidence for a new binding mode to GSK-3: allosteric regulation by the marine compound palinurin.
Glycogen synthase kinase 3β (GSK-3β) is widely recognised as a relevant player in the pathogenesis of several highly prevalent disorders such as Alzheimer's disease, mood disorders, diabetes and cancer. Therefore, this enzyme constitutes a highly attractive therapeutic target for the development of selective inhibitors as new promising drugs for the treatment of these pathologies. We describe here the isolation and biochemical characterization of the marine natural sesquiterpene palinurin as a GSK-3β inhibitor. Experimental studies performed for characterizing the inhibitory mechanism indicate that GSK-3β inhibition by palinurin cannot be competed out by ATP nor peptide substrate. Molecular modelling techniques have enabled us to propose an unconventional binding mode to GSK-3β. Moreover, molecular dynamics simulations have identified an allosteric mechanism by which binding of palinurin leads to GSK-3β inhibition. The inhibitory activities determined for a series of structurally related analogues support the proposed binding mode of palinurin, which is the first compound described to target this allosteric site. The results offer new opportunities for designing and developing selective inhibitors with novel mechanisms of action.
Departament de Fisicoquímica and Institut de Biomedicina (IBUB), Facultat de Farmàcia, Universitat de Barcelona, Campus de l'Alimentaió de Torribera, Prat de Riba 171, Edifici Verdaguer, 08921 Santa Coloma de Gramanet, Spain. abidonchanalb@ub.edu
Axel
A
Bidon-Chanal
Ana
A
Fuertes
Diana
D
Alonso
Daniel I
DI
Pérez
Ana
A
Martínez
F Javier
FJ
Luque
Miguel
M
Medina
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; C542546:palinurin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D015107:4-Butyrolactone