6hhp

Ternary complex of Estrogen Receptor alpha peptide and 14-3-3 sigma C42 mutant bound to disulfide fragment PPI stabilizer 1

spinqualitylabelsall models 6hhp, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6hhp is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.802Å Ligands: G4Z, MG, TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Modulation of protein-protein interactions (PPIs) by small molecules has emerged as a valuable approach in drug discovery. Compared to direct inhibition, PPI stabilization is vastly underexplored but has strong advantages, including the ability to gain selectivity by targeting an interface formed only upon association of proteins. Here, we present the application of a site-directed screening technique based on disulfide trapping (tethering) to select for fragments that enhance the affinity between protein partners. We target the phosphorylation-dependent interaction between the hub protein 14-3-3sigma and a peptide derived from Estrogen Receptor alpha (ERalpha), an important breast cancer target that is negatively regulated by 14-3-3sigma. We identify orthosteric stabilizers that increase 14-3-3/ERalpha affinity up to 40-fold and propose the mechanism of stabilization based on X-ray crystal structures. These fragments already display partial selectivity toward ERalpha-like motifs over other representative 14-3-3 clients. This first of its kind study illustrates the potential of the tethering approach to overcome the hurdles in systematic PPI stabilizer discovery. Site-Directed Fragment-Based Screening for the Discovery of Protein-Protein Interaction Stabilizers.,Sijbesma E, Hallenbeck KK, Leysen S, de Vink PJ, Skora L, Jahnke W, Brunsveld L, Arkin MR, Ottmann C J Am Chem Soc. 2019 Feb 19. doi: 10.1021/jacs.8b11658. PMID:30707565 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also 14-3-3 protein 3D structures

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