6TJM

Crystal structure of an Estrogen Receptor alpha 8-mer phosphopeptide in complex with 14-3-3sigma stabilized by Pyrrolidone1

Summary for 6TJM

• Entry DOI: 10.2210/pdb6tjm/pdb
• Descriptor: 14-3-3 protein sigma, C-terminal phosphopeptide of human estrogen receptor alpha, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: estrogen receptor, 14-3-3, ppi, stabiliser, complex, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 27924.49

Authors

Andrei, S.A.,Bosica, F.,Ottmann, C.,O'Mahony, G. (deposition date: 2019-11-26, release date: 2020-04-29, Last modification date: 2024-11-13)

Primary citation

Bosica, F.,Andrei, S.A.,Neves, J.F.,Brandt, P.,Gunnarsson, A.,Landrieu, I.,Ottmann, C.,O'Mahony, G.
Design of Drug-Like Protein-Protein Interaction Stabilizers Guided By Chelation-Controlled Bioactive Conformation Stabilization.
Chemistry, 26:7131-7139, 2020

PubMed Abstract: Protein-protein interactions (PPIs) of 14-3-3 proteins are a model system for studying PPI stabilization. The complex natural product Fusicoccin A stabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies, motivating the search for more drug-like chemical matter. However, drug-like 14-3-3 PPI stabilizers enabling such studies have remained elusive. An X-ray crystal structure of a PPI in complex with an extremely low potency stabilizer uncovered an unexpected non-protein interacting, ligand-chelated Mg leading to the discovery of metal-ion-dependent 14-3-3 PPI stabilization potency. This originates from a novel chelation-controlled bioactive conformation stabilization effect. Metal chelation has been associated with pan-assay interference compounds (PAINS) and frequent hitter behavior, but chelation can evidently also lead to true potency gains and find use as a medicinal chemistry strategy to guide compound optimization. To demonstrate this, we exploited the effect to design the first potent, selective, and drug-like 14-3-3 PPI stabilizers.

PubMed: 32255539
DOI: 10.1002/chem.202001608

Experimental method

X-RAY DIFFRACTION (1.85 Å)