8BTQ

Small molecule stabilizer for 14-3-3/ChREBP (Cmd1-soaking)

Summary for 8BTQ

• Entry DOI: 10.2210/pdb8btq/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: 29434.00

Authors

Pennings, M.A.M.,Visser, E.J.,Ottmann, C. (deposition date: 2022-11-29, 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) with two major splice isoforms (α and β). In chronic hyperglycemia and glucolipotoxicity, ChREBPα-mediated ChREBPβ expression surges, leading to insulin-secreting β-cell dedifferentiation and death. 14-3-3 binding to ChREBPα results in cytoplasmic retention and suppression of transcriptional activity. Thus, small molecule-mediated stabilization of this protein-protein interaction (PPI) may be of therapeutic value. Here, we show that structure-based optimizations of a 'molecular glue' compound led to potent ChREBPα/14-3-3 PPI stabilizers with cellular activity. In primary human β-cells, the most active compound retained ChREBPα in the cytoplasm, and efficiently protected β-cells 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 to target TFs.

PubMed: 38405965
DOI: 10.1101/2024.02.16.580675

Experimental method

X-RAY DIFFRACTION (1.6 Å)