Elucidating Substrate and Inhibitor Binding Sites on the Surface of GSK-3β and the Refinement of a Competitive Inhibitor

Licht-Murava, Avital; Plotkin, Batya; Eisenstein, Miriam; Eldar-Finkelman, Hagit

doi:10.1016/j.jmb.2011.02.036

Cited by 22 publications

(23 citation statements)

References 53 publications

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“…A combined approach of mutagenesis and computational protein–protein docking analyses identified a novel substrate-binding site within the catalytic core of GSK-3β formed by Phe 67, Gln 89, Phe93, and Asn 95 (Ilouz et al, 2006; Licht-Murava et al, 2011), and Asp 181 as an additional binding site for the N-terminal pseudosubstrate (Ilouz et al, 2008; Figure 3B). These residues are spatially located near the ATP-binding site and the phosphate binding pocket that interacts with the phospho-serine moiety of the substrate (Dajani et al, 2001; ter Haar et al, 2001; Figure 3B).…”

Section: Organic Molecules As Gsk-3 Inhibitorsmentioning

confidence: 99%

“…From studies of the binding mode of L803-mts with GSK-3 it was found that the inhibitor- and substrate-binding sites are not identical. Both substrate and L803-mts interact with the phosphate binding pocket, but the substrate interacts with the cavity bordered by Gln 89 and Asn 95, whereas L803-mts mainly interacts with Phe 93 and with a hydrophobic surface located away from the ATP-binding site (Licht-Murava et al, 2011; Figure 3B). This clarified our understanding of the different binding modes of substrates and inhibitors.…”

Section: Organic Molecules As Gsk-3 Inhibitorsmentioning

confidence: 99%

“…Contacts other than those used by the substrate may be crucial for converting a substrate to an inhibitor. Based on this idea, new L803-mts variants were synthesized, and some were 3- to 10-fold better inhibitors than L803-mts (Licht-Murava et al, 2011). Taken together, substrate–competitive inhibitors of GSK-3 hold tremendous promise as potential therapeutics.…”

Section: Organic Molecules As Gsk-3 Inhibitorsmentioning

confidence: 99%

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GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

Eldar-Finkelman

Martı́nez

2011

Front. Mol. Neurosci.

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303

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Inhibiting glycogen synthase kinase-3 (GSK-3) activity via pharmacological intervention has become an important strategy for treating neurodegenerative and psychiatric disorders. The known GSK-3 inhibitors are of diverse chemotypes and mechanisms of action and include compounds isolated from natural sources, cations, synthetic small-molecule ATP-competitive inhibitors, non-ATP-competitive inhibitors, and substrate–competitive inhibitors. Here we describe the variety of GSK-3 inhibitors with a specific emphasis on their biological activities in neurons and neurological disorders. We further highlight our current progress in the development of non-ATP-competitive inhibitors of GSK-3. The available data raise the hope that one or more of these drug design approaches will prove successful at stabilizing or even reversing the aberrant neuropathology and cognitive deficits of certain central nervous system disorders.

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Section: Organic Molecules As Gsk-3 Inhibitorsmentioning

confidence: 99%

Section: Organic Molecules As Gsk-3 Inhibitorsmentioning

confidence: 99%

Section: Organic Molecules As Gsk-3 Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

Eldar-Finkelman

Martı́nez

2011

Front. Mol. Neurosci.

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303

278

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“…Other GSK3 inhibitors that are not competitive with the ATP binding site in GSK3 are particularly promising (Eldar-Finkelman and Martinez, 2011). L803-mts is a cell-permeable, 11 residue peptide that is a substrate-competitive specific inhibitor of GSK3 (Plotkin et al, 2003; Kaidanovich-Beilin et al, 2004; Licht-Murava et al, 2011). TDZD-8 is a highly selective ATP non-competitive inhibitor of GSK3 (Martinez et al, 2002).…”

Section: Gsk3 and Inhibitorsmentioning

confidence: 99%

Glycogen synthase kinase-3 inhibitors: Rescuers of cognitive impairments

King

Pardo

Cheng

et al. 2014

Pharmacology & Therapeutics

157

112

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Impairment of cognitive processes is a devastating outcome of many diseases, injuries, and drugs affecting the central nervous system (CNS). Most often, very little can be done by available therapeutic interventions to improve cognitive functions. Here we review evidence that inhibition of glycogen synthase kinase-3 (GSK3) ameliorates cognitive deficits in a wide variety of animal models of CNS diseases, including Alzheimer's disease, Fragile X syndrome, Down syndrome, Parkinson's disease, spinocerebellar ataxia type 1, traumatic brain injury, and others. GSK3 inhibitors also improve cognition following impairments caused by therapeutic interventions, such as cranial irradiation for brain tumors. These findings demonstrate that GSK3 inhibitors are able to ameliorate cognitive impairments caused by a diverse array of diseases, injury, and treatments. The improvements in impaired cognition instilled by administration of GSK3 inhibitors appear to involve a variety of different mechanisms, such as supporting long-term potentiation and diminishing long-term depression, promotion of neurogenesis, reduction of inflammation, and increasing a number of neuroprotective mechanisms. The potential for GSK3 inhibitors to repair cognitive deficits associated with many conditions warrants further investigation of their potential for therapeutic interventions, particularly considering the current dearth of treatments available to reduce loss of cognitive functions.

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“…Substrate‐competitive inhibitors particularly are now being developed to this end (e.g. Bogoyevitch and Arthur, 2008; Licht‐Murava et al ., 2011) and are providing promising leads. In time, this approach will likely be applied to the IKKs.…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

Inhibitory kappa B kinases as targets for pharmacological regulation

Gamble

McIntosh

Scott

et al. 2012

British J Pharmacology

102

106

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The inhibitory kappa B kinases (IKKs) are well recognized as key regulators of the nuclear factor kappa B (NF-kB) cascade and as such represent a point of convergence for many extracellular agents that activate this pathway. The IKKs generally serve to transduce pro-inflammatory and growth stimulating signals that contribute to major cellular processes but also play a key role in the pathogenesis of a number of human diseases. Therefore, the catalytic IKKs represent attractive targets for intervention with small molecule kinase inhibitors. IKK isoforms are assembled as variable multi-subunit IKK complexes that regulate not only NF-kB dimers, but also protein substrates out-with this cascade. Consequently, close consideration of how these individual complexes transduce extracellular signals and more importantly what impact small molecule inhibitors of the IKKs have on functional outcomes are demanded. A number of adenosine triphosphate (ATP)-competitive IKKb-selective inhibitors have been developed but have demonstrated a lack of activity against IKKa. A number of these chemicals have also exhibited detrimental outcomes such as cellular toxicity and immuno-suppression. The impact of small molecule inhibitors of IKK catalytic activity will therefore be reappraised, examining the advantages and potential disadvantages to this type of intervention strategy in the treatment of diseases such as arthritis, intestinal inflammation and cancer. Furthermore, we will outline some emerging strategies, particularly the disruption of protein-protein interactions within the IKK complex, as an alternative route towards the development of novel pharmacological agents. Whether these alternatives may negate the limitations of ATP-competitive molecules and potentially avoid the issues of toxicity will be discussed.

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Elucidating Substrate and Inhibitor Binding Sites on the Surface of GSK-3β and the Refinement of a Competitive Inhibitor

Cited by 22 publications

References 53 publications

GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

Glycogen synthase kinase-3 inhibitors: Rescuers of cognitive impairments

Inhibitory kappa B kinases as targets for pharmacological regulation

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