8BX4

fragment-linked stabilizer for ERa - 14-3-3 interaction (1074392)

Summary for 8BX4

• Entry DOI: 10.2210/pdb8bx4/pdb
• Descriptor: 14-3-3 protein sigma, ERalpha peptide, 2-[3,4-bis(chloranyl)phenoxy]-~{N}-[3-(5-carbamimidoylthiophen-3-yl)phenyl]-2-methyl-propanamide, ... (4 entities in total)
• Functional Keywords: 14-3-3, era, fragment linking, stabilization, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 27604.88

Authors

Visser, E.J.,Vandenboorn, E.M.F.,Ottmann, C. (deposition date: 2022-12-07, release date: 2023-08-02, Last modification date: 2024-11-20)

Primary citation

Visser, E.J.,Jaishankar, P.,Sijbesma, E.,Pennings, M.A.M.,Vandenboorn, E.M.F.,Guillory, X.,Neitz, R.J.,Morrow, J.,Dutta, S.,Renslo, A.R.,Brunsveld, L.,Arkin, M.R.,Ottmann, C.
From Tethered to Freestanding Stabilizers of 14-3-3 Protein-Protein Interactions through Fragment Linking.
Angew.Chem.Int.Ed.Engl., 62:e202308004-e202308004, 2023

PubMed Abstract: Small-molecule stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. However, the systematic discovery of PPI stabilizers remains a largely unmet challenge. Herein we report a fragment-linking approach targeting the interface of 14-3-3 and a peptide derived from the estrogen receptor alpha (ERα) protein. Two classes of fragments-a covalent and a noncovalent fragment-were co-crystallized and subsequently linked, resulting in a noncovalent hybrid molecule in which the original fragment interactions were largely conserved. Supported by 20 crystal structures, this initial hybrid molecule was further optimized, resulting in selective, 25-fold stabilization of the 14-3-3/ERα interaction. The high-resolution structures of both the single fragments, their co-crystal structures and those of the linked fragments document a feasible strategy to develop orthosteric PPI stabilizers by linking to an initial tethered fragment.

PubMed: 37455289
DOI: 10.1002/anie.202308004

Experimental method

X-RAY DIFFRACTION (1.6 Å)