9I6T
14-3-3sigma binding to the ERa peptide and compound 32
This is a non-PDB format compatible entry.
Summary for 9I6T
| Entry DOI | 10.2210/pdb9i6t/pdb |
| Descriptor | 14-3-3 protein sigma, Estrogen receptor, 2-chloranyl-~{N}-[[4-[3-[(2-chloranyl-6-methyl-phenyl)amino]imidazo[1,2-a]pyridin-2-yl]phenyl]methyl]ethanamide, ... (6 entities in total) |
| Functional Keywords | 14-3-3, protein-protein interactions, stabilization, peptide binding protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 27751.53 |
| Authors | |
| Primary citation | Konstantinidou, M.,Zingiridis, M.,Pennings, M.A.M.,Fragkiadakis, M.,Virta, J.M.,Revalde, J.L.,Visser, E.J.,Ottmann, C.,Brunsveld, L.,Neochoritis, C.G.,Arkin, M.R. Scaffold-hopping for molecular glues targeting the 14-3-3/ER alpha complex. Nat Commun, 16:6467-6467, 2025 Cited by PubMed Abstract: Molecular glues, small molecules that bind cooperatively at a protein-protein interface, have emerged as powerful modalities for the modulation of protein-protein interactions (PPIs) and "undruggable" targets. The systematic identification of new chemical matter with a molecular glue mechanism of action remains a significant challenge in drug discovery. Here, we present a scaffold hopping approach, using as a starting point our previously developed molecular glues for the native 14-3-3/estrogen receptor alpha (ERα) complex. The novel, computationally designed scaffold is based on the Groebke-Blackburn-Bienaymé multi-component reaction (MCR), leading to drug-like analogs with multiple points of variation, thus enabling the rapid derivatization and optimization of the scaffold. Structure-activity relationships (SAR) are developed using orthogonal biophysical assays, such as intact mass spectrometry, TR-FRET and SPR. Rational structure-guided optimization is facilitated by multiple crystal structures of ternary complexes with the glues, 14-3-3 and phospho-peptides mimicking the highly disordered C-terminus of ERα. Cellular stabilization of 14-3-3/ERα for the most potent analogs is confirmed using a NanoBRET assay with full-length proteins in live cells. Our approach highlights the potential of MCR chemistry, combined with scaffold hopping, to drive the development and optimization of unprecedented molecular glue scaffolds. PubMed: 40659654DOI: 10.1038/s41467-025-61176-4 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.3 Å) |
Structure validation
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