Life Sciences and cultural heritage Figure 1. (a) This image shows the interaction between the phospholipase NAPE-PLD (the two protein dimer subunits are depicted in light and dark gray) of the endocannabinoid system and membrane phospholipids (molecules in yellow-orange), which is mediated by bile acid molecules (green). Bound bile acid molecules structurally enhance the dimer assembly, promote membrane interaction (that allows the phospholipase to get its substrate), and are essential for the enzyme catalysis that generates products (fatty acid ethanolamides) that elicit a broad range of key protective roles for diseases. The structural model of the complex was obtained combining results from studies of single particle cryo-electron microscopy and x-ray diffraction at Elettra. The crystal structure shows how the thiazide drug (magenta) bounds to the internal dimer channel of NAPE-PLD. (b) The discovery and validation of NAPE-PLD as target of thiazide diuretics shed light on the mechanism of treatment of hypertension, identify NAPE-PLD as novel therapeutic target for cardiovascular and neurovascular diseases, and indicate an innovative way to modulate efficaciously the endocannabinoid system in therapy. (c) This image shows the surface interaction area between the two dimer subunits of NAPE-PLD with the bound drug molecule using a slice plane joined to a graphic illustration of its therapeutic implications. Adapted from S. Chiarugi et al. Cell Chem Biol 32 (449), with permission from Cell Chemical Biology. F. Margheriti1,2, S. Chiarugi1,2, R. Marotta3, A. Chaves-Sanjuan4,5, M. Bolognesi4,5, R. Scuri6, G. Garau1,2,7 1 Italian Institute of Technology (IIT@NEST), Pisa, Italy 2 Laboratorio NEST, Scuola Normale Superiore di Pisa, Italy 3 Italian Institute of Technology (IIT), Genoa, Italy 4 Department of Biosciences, University of Milano, Italy 5 Pediatric Research Center Fond. Invernizzi and Nolimits Center, University of Milan, Italy 6 Dept Translational Res New Technologies in Medicine and Surgery, University of Pisa, Italy 7 Laboratori ALIVEDA, Pisa, Italy e-mail: gianpierogarau@gmail.com Acknowledgments We thank the Synchrotron Elettra (Trieste, IT) XRD2 beamline staff, Dr Nicola Demitri and Dr Anne Heroux. We express our gratitude to Prof Gabriel A. Frank, Ben-Gurion University of the Negev (Ben-Gurion, IL). Part of this work was carried out at NOLIMITS, an advanced imaging facility established by the Università degli Studi di Milano. This work was initially supported by the Agreement on Industrial, Scientific and Technological Research and Development Cooperation between the Israeli Ministry of Science, Technology and Space (MOST) and the Ministero Italiano degli Affari Esteri e della Cooperazione Internazionale (MAECI) (to G. G. Project: SB2D-CNI-BGU). Original paper S. Chiarugi et al. Cell Chem Biol 32 (449); DOI: 10.1016/j.chembiol.2025.01.008 Fig. 1 membrane phospholipids Bile Acids NAPE-PLD Thiazide Drug a b Thiazide Drug c Elettra Highlights 2024–2025 73
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