8BWH

Small molecule stabilizer for 14-3-3/ChREBP (Cmd 42)

Summary for 8BWH

• Entry DOI: 10.2210/pdb8bwh/pdb
• Descriptor: 14-3-3 protein sigma, Carbohydrate-responsive element-binding protein, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: 14-3-3, chrebp, stabilization, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 29388.85

Authors

Pennings, M.A.M.,Visser, E.J.,Ottmann, C. (deposition date: 2022-12-06, release date: 2024-05-01)

Primary citation

Katz, L.S.,Visser, E.J.,Plitzko, K.F.,Pennings, M.,Cossar, P.J.,Tse, I.L.,Kaiser, M.,Brunsveld, L.,Scott, D.K.,Ottmann, C.
Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity.
Biorxiv, 2024

PubMed Abstract: The Carbohydrate Response Element Binding Protein (ChREBP) is a glucose-responsive transcription factor (TF) that is characterized by two major splice isoforms (α and β). In acute hyperglycemia, both ChREBP isoforms regulate adaptive β-expansion; however, during chronic hyperglycemia and glucolipotoxicity, ChREBPβ expression surges, leading to β-cell dedifferentiation and death. 14-3-3 binding to ChREBPα results in its cytoplasmic retention and concomitant suppression of transcriptional activity, suggesting that small molecule-mediated stabilization of this protein-protein interaction (PPI) via molecular glues may represent an attractive entry for the treatment of metabolic disease. Here, we show that structure-based optimizations of a molecular glue tool compound led not only to more potent ChREBPα/14-3-3 PPI stabilizers but also for the first time cellular active compounds. In primary human β-cells, the most active compound stabilized the ChREBPα/14-3-3 interaction and thus induced cytoplasmic retention of ChREBPα, resulting in highly efficient β-cell protection from glucolipotoxicity while maintaining β-cell identity. This study may thus not only provide the basis for the development of a unique class of compounds for the treatment of Type 2 Diabetes but also showcases an alternative 'molecular glue' approach for achieving small molecule control of notoriously difficult targetable TFs.

PubMed: 38405965
DOI: 10.1101/2024.02.16.580675

Experimental method

X-RAY DIFFRACTION (2.1 Å)