7sxf
From Proteopedia
BIO-2895 (BRD0705) bound GSK3alpha-axin complex
Structural highlights
FunctionGSK3A_HUMAN Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1 (PubMed:11749387, PubMed:17478001, PubMed:19366350). Requires primed phosphorylation of the majority of its substrates (PubMed:11749387, PubMed:17478001, PubMed:19366350). Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:11749387, PubMed:17478001, PubMed:19366350). Regulates glycogen metabolism in liver, but not in muscle (By similarity). May also mediate the development of insulin resistance by regulating activation of transcription factors (PubMed:10868943, PubMed:17478001). In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin (PubMed:17229088). Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease (PubMed:12761548). May be involved in the regulation of replication in pancreatic beta-cells (By similarity). Is necessary for the establishment of neuronal polarity and axon outgrowth (By similarity). Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions which activates KAT5/TIP60 acetyltransferase activity and promotes acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (By similarity). Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075).[UniProtKB:P18265][UniProtKB:P49841][UniProtKB:Q2NL51][1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedGlycogen synthase kinase 3 (GSK3) remains a therapeutic target of interest for diverse clinical indications. However, one hurdle in the development of small molecule GSK3 inhibitors has been safety concerns related to pan-inhibition of both GSK3 paralogs, leading to activation of the Wnt/beta-catenin pathway and potential for aberrant cell proliferation. Development of GSK3alpha or GSK3beta paralog-selective inhibitors that could offer an improved safety profile has been reported but further advancement has been hampered by the lack of structural information for GSK3alpha. Here we report for the first time the crystal structure for GSK3alpha, both in apo form and bound to a paralog-selective inhibitor. Taking advantage of this new structural information, we describe the design and in vitro testing of novel compounds with up to approximately 37-fold selectivity for GSK3alpha over GSK3beta with favorable drug-like properties. Furthermore, using chemoproteomics, we confirm that acute inhibition of GSK3alpha can lower tau phosphorylation at disease-relevant sites in vivo, with a high degree of selectivity over GSK3beta and other kinases. Altogether, our studies advance prior efforts to develop GSK3 inhibitors by describing GSK3alpha structure and novel GSK3alpha inhibitors with improved selectivity, potency, and activity in disease-relevant systems. Elucidation of the GSK3alpha Structure Informs the Design of Novel, Paralog-Selective Inhibitors.,Amaral B, Capacci A, Anderson T, Tezer C, Bajrami B, Lulla M, Lucas B, Chodaparambil JV, Marcotte D, Kumar PR, Murugan P, Spilker K, Cullivan M, Wang T, Peterson AC, Enyedy I, Ma B, Chen T, Yousaf Z, Calhoun M, Golonzhka O, Dillon GM, Koirala S ACS Chem Neurosci. 2023 Mar 15;14(6):1080-1094. doi: , 10.1021/acschemneuro.2c00476. Epub 2023 Feb 22. PMID:36812145[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
