Targeting the phosphoprotein enriched in diabetes/astrocytes 15 death effector domain via fragment-based and integrative structural biology approaches.

Authors

Ivan Mercurio, Federica Carucci, Vittoria Nanna, Sara Di Marino, Maria Giovanna Eva Papadopoulos, Martina Bischetti, Francesca Fata, Gaetano Malgieri, Dritan Siliqi, Alessandro Piai, Roberto Fattorusso, Giuseppe Felice Mangiatordi, Carlo Toniatti, Michele Saviano, Domenico Alberga

Published in

International journal of biological macromolecules. Pages 154849. Oct 16, 2026. Epub Oct 16, 2026.

Abstract

Phosphoprotein Enriched in Diabetes/Astrocytes 15 (PED/PEA-15) is a 15 kDa adaptor protein whose overexpression drives tumorigenesis and type II diabetes through dysregulated protein-protein interactions (PPIs) mediated by its Death Effector Domain (DED). Despite its therapeutic relevance, no potent small-molecule inhibitors targeting the DED have yet been identified. Here, we employed a fragment-based drug discovery approach combining ¹⁹F and ¹H NMR screening of a 118-compound fluorinated library to identify F2 a fragment that binds the PED/PEA-15 DED with an estimated dissociation constant of 150 μM. NMR chemical shift perturbation analysis mapped the binding site to the α2-α3 loop, α3, and α5 helices. To better characterise the protein, Small-angle X-ray scattering of the apo protein was employed, yielding a structural model in which the C-terminal tail is consistent with a conformation that is not maximally extended. Induced fit docking and molecular dynamics simulations of the PED/PEA-15-F2 complex supported a plausible binding pose and suggested a ligand-induced destabilisation of the α3 helix propagating to the α6 helix. Correlation network analysis further suggests a hypothesis in which F2 rewires the dynamic architecture of the DED and alters allosteric communication between residues of the DED and the C-terminal tail. The identification of a ligand-accessible site on the DED supports the druggability of PED/PEA-15 and provides a refined structural framework for fragment optimisation and for testing whether engagement of this site can be translated into modulation of PED/PEA-15 PPIs with therapeutic potential in cancer and type II diabetes.

PMID:
42887742
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.

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