8adm

Ternary complex of 14-3-3 sigma, Usp8pS718 phosphopeptide and small molecule stabilizer

spinqualitylabelsall models 8adm, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8adm 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 1.7Å Ligands: O6C, SEP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Dysregulation of protein-protein interactions (PPIs) commonly leads to disease. PPI stabilization has only recently been systematically explored for drug discovery despite being a powerful approach to selectively target intrinsically disordered proteins and hub proteins, like 14-3-3, with multiple interaction partners. Disulfide tethering is a site-directed fragment-based drug discovery (FBDD) methodology for identifying reversibly covalent small molecules. We explored the scope of disulfide tethering for the discovery of selective PPI stabilizers (molecular glues) using the hub protein 14-3-3sigma. We screened complexes of 14-3-3 with 5 biologically and structurally diverse phosphopeptides derived from the 14-3-3 client proteins ERalpha, FOXO1, C-RAF, USP8, and SOS1. Stabilizing fragments were found for 4/5 client complexes. Structural elucidation of these complexes revealed the ability of some peptides to conformationally adapt to make productive interactions with the tethered fragments. We validated eight fragment stabilizers, six of which showed selectivity for one phosphopeptide client, and structurally characterized two nonselective hits and four fragments that selectively stabilized C-RAF or FOXO1. The most efficacious fragment increased 14-3-3sigma/C-RAF phosphopeptide affinity by 430-fold. Disulfide tethering to the wildtype C38 in 14-3-3sigma provided diverse structures for future optimization of 14-3-3/client stabilizers and highlighted a systematic method to discover molecular glues. A Systematic Approach to the Discovery of Protein-Protein Interaction Stabilizers.,Kenanova DN, Visser EJ, Virta JM, Sijbesma E, Centorrino F, Vickery HR, Zhong M, Neitz RJ, Brunsveld L, Ottmann C, Arkin MR ACS Cent Sci. 2023 Apr 18;9(5):937-946. doi: 10.1021/acscentsci.2c01449. , eCollection 2023 May 24. PMID:37252362 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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