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7BDT

14-3-3 sigma with Pin1 binding site pS72 and covalently bound LvD1009

Summary for 7BDT
Entry DOI10.2210/pdb7bdt/pdb
Related7AOG
Descriptor14-3-3 protein sigma, Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, 2-bromanyl-4-(2-phenylimidazol-1-yl)benzaldehyde, ... (5 entities in total)
Functional Keywords1433, peptide binding protein, peptidyl-prolyl cis-trans isomerase nima-interacting 1
Biological sourceHomo sapiens (Human)
More
Total number of polymer chains2
Total formula weight30716.33
Authors
Wolter, M.,Dijck, L.v.,Cossar, P.J.,Ottmann, C. (deposition date: 2020-12-22, release date: 2021-06-16, Last modification date: 2024-11-06)
Primary citationCossar, P.J.,Wolter, M.,van Dijck, L.,Valenti, D.,Levy, L.M.,Ottmann, C.,Brunsveld, L.
Reversible Covalent Imine-Tethering for Selective Stabilization of 14-3-3 Hub Protein Interactions.
J.Am.Chem.Soc., 143:8454-8464, 2021
Cited by
PubMed Abstract: The stabilization of protein complexes has emerged as a promising modality, expanding the number of entry points for novel therapeutic intervention. Targeting proteins that mediate protein-protein interactions (PPIs), such as hub proteins, is equally challenging and rewarding as they offer an intervention platform for a variety of diseases, due to their large interactome. 14-3-3 hub proteins bind phosphorylated motifs of their interaction partners in a conserved binding channel. The 14-3-3 PPI interface is consequently only diversified by its different interaction partners. Therefore, it is essential to consider, additionally to the potency, also the selectivity of stabilizer molecules. Targeting a lysine residue at the interface of the composite 14-3-3 complex, which can be targeted explicitly via aldimine-forming fragments, we studied the design of PPI stabilizers under consideration of potential selectivity. By applying cooperativity analysis of ternary complex formation, we developed a reversible covalent molecular glue for the 14-3-3/Pin1 interaction. This small fragment led to a more than 250-fold stabilization of the 14-3-3/Pin1 interaction by selective interfacing with a unique tryptophan in Pin1. This study illustrates how cooperative complex formation drives selective PPI stabilization. Further, it highlights how specific interactions within a hub proteins interactome can be stabilized over other interactions with a common binding motif.
PubMed: 34047554
DOI: 10.1021/jacs.1c03035
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.75 Å)
Structure validation

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PDB entries from 2024-11-06

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