8a9g
Binary complex of 14-3-3 zeta Glucocorticoid Receptor (GR) pT524 peptide stabilised by (R)-para chloropyrrolidone1
Structural highlights
Function1433Z_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe 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 alpha (ERalpha) 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. Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein-Protein Interaction.,Pallesen JS, Munier CC, Bosica F, Andrei SA, Edman K, Gunnarsson A, La Sala G, Putra OD, Srdanovic S, Wilson AJ, Wissler L, Ottmann C, Perry MWD, O'Mahony G J Med Chem. 2022 Dec 9. doi: 10.1021/acs.jmedchem.2c01635. PMID:36484727[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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