7B9M

Cys-45-tethered stabilizer 3 of 14-3-3(sigma)/ERa PPI

Summary for 7B9M

• Entry DOI: 10.2210/pdb7b9m/pdb
• Descriptor: 14-3-3 protein sigma, Estrogen receptor, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: protein-protein interaction; stabilization; hub protein; transcription factor, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 27803.81

Authors

Sijbesma, E.,Ottmann, C. (deposition date: 2020-12-14, release date: 2021-07-07, Last modification date: 2024-11-13)

Primary citation

Sijbesma, E.,Hallenbeck, K.K.,Andrei, S.A.,Rust, R.R.,Adriaans, J.M.C.,Brunsveld, L.,Arkin, M.R.,Ottmann, C.
Exploration of a 14-3-3 PPI Pocket by Covalent Fragments as Stabilizers.
Acs Med.Chem.Lett., 12:976-982, 2021

PubMed Abstract: The systematic discovery of functional fragments binding to the composite interface of protein complexes is a first critical step for the development of orthosteric stabilizers of protein-protein interactions (PPIs). We have previously shown that disulfide trapping successfully yielded covalent stabilizers for the PPI of 14-3-3 with the estrogen receptor ERα. Here we provide an assessment of the composite PPI target pocket and the molecular characteristics of various fragments binding to a specific subpocket. Evaluating structure-activity relationships highlights the basic principles for PPI stabilization by these covalent fragments that engage a relatively large and exposed binding pocket at the protein/peptide interface with a "molecular glue" mode of action.

PubMed: 34136078
DOI: 10.1021/acsmedchemlett.1c00088

Experimental method

X-RAY DIFFRACTION (1.7 Å)