7C8E

Crystal Structure of 14-3-3 epsilon with 9J10 peptide

Summary for 7C8E

• Entry DOI: 10.2210/pdb7c8e/pdb
• Descriptor: 14-3-3 protein epsilon, 9J10, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (4 entities in total)
• Functional Keywords: signaling protein, phosphopeptide binding, peptide complex, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 63511.88

Authors

Mathivanan, S.,Sudhakar, S.,Bairy, S.,Kamariah, N.,Venkitaraman, A. (deposition date: 2020-05-30, release date: 2021-06-02, Last modification date: 2024-10-09)

Primary citation

Emery, A.,Hardwick, B.S.,Crooks, A.T.,Milech, N.,Watt, P.M.,Mithra, C.,Kumar, V.,Giridharan, S.,Sadasivam, G.,Mathivanan, S.,Sudhakar, S.,Bairy, S.,Bharatham, K.,Hurakadli, M.A.,Prasad, T.K.,Kamariah, N.,Muellner, M.,Coelho, M.,Torrance, C.J.,McKenzie, G.J.,Venkitaraman, A.R.
Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library.
Cell Chem Biol, 28:1602-1615.e9, 2021

PubMed Abstract: Genetic screening technologies to identify and validate macromolecular interactions (MMIs) essential for complex pathways remain an important unmet need for systems biology and therapeutics development. Here, we use a library of peptides from diverse prokaryal genomes to screen MMIs promoting the nuclear relocalization of Forkhead Box O3 (FOXO3a), a tumor suppressor more frequently inactivated by post-translational modification than mutation. A hit peptide engages the 14-3-3 family of signal regulators through a phosphorylation-dependent interaction, modulates FOXO3a-mediated transcription, and suppresses cancer cell growth. In a crystal structure, the hit peptide occupies the phosphopeptide-binding groove of 14-3-3ε in a conformation distinct from its natural peptide substrates. A biophysical screen identifies drug-like small molecules that displace the hit peptide from 14-3-3ε, providing starting points for structure-guided development. Our findings exemplify "protein interference," an approach using evolutionarily diverse, natural peptides to rapidly identify, validate, and develop chemical probes against MMIs essential for complex cellular phenotypes.

PubMed: 34111400
DOI: 10.1016/j.chembiol.2021.05.009

Experimental method

X-RAY DIFFRACTION (3.16 Å)