7PWT

Crystal structure of 14-3-3 sigma in complex with a C-terminal Estrogen Receptor alpha phosphopeptide, stabilised by pyrrolidone derivative 228

Summary for 7PWT

• Entry DOI: 10.2210/pdb7pwt/pdb
• Descriptor: 14-3-3 protein sigma, C-terminus of Estrogen receptor alpha, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: nuclear receptor, phosphorylation, trafficking, ppi stabiliser, chaperone
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 27854.44

Authors

Andrei, S.A.,Bosica, F.,O'Mahony, G.,Ottmann, C. (deposition date: 2021-10-07, release date: 2022-12-21, Last modification date: 2024-10-09)

Primary citation

Pallesen, J.S.,Munier, C.C.,Bosica, F.,Andrei, S.A.,Edman, K.,Gunnarsson, A.,La Sala, G.,Putra, O.D.,Srdanovic, S.,Wilson, A.J.,Wissler, L.,Ottmann, C.,Perry, M.W.D.,O'Mahony, G.
Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein-Protein Interaction.
J.Med.Chem., 65:16818-16828, 2022

PubMed Abstract: The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein-protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators.

PubMed: 36484727
DOI: 10.1021/acs.jmedchem.2c01635

Experimental method

X-RAY DIFFRACTION (2.312 Å)