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Progetti in evidenza
Progetti  INCIPIT ISTAPCA LightDyNAmics Fondo Europeo Pesca INMiND Fondazione Veronesi Instruct-IT Euro-BioImaging PRIN eHealthNet Ponrec MFAG Grant MERITCollegamenti
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Cationic porphyrins are tunable gatekeepers of the 20S proteasome (441 visite) (PDF privato 108 visite) Chemical Science (ISSN: 2041-6539, 2041-6520), 2016; 7(2): 1286-1297. Tipo di articolo: Journal Article, Impact factor: 8.668 Impact factor a 5 anni: 8.733 Parole chiave: Aromatic Compounds, Binding Energy, Bioinformatics, Enzyme Kinetics, Isomers, Porphyrins, Reconfigurable Hardware, Aromatic Residues, Bioinformatic Analysis, Catalytic Chambers, Cationic Porphyrin, Gating Mechanisms, Ligand Interactions, Negatively Charged, Regulatory Mechanism, Enzyme Inhibition, Url: http://dx.doi.org/10.1039/C5SC03312H The 20S proteasome is a barrel-shaped enzymatic assembly playing a critical role in proteome maintenance. Access of proteasome substrates to the catalytic chamber is finely regulated through gating mechanisms which involve aromatic and negatively charged residues located at the N-terminal tails of α subunits. However, despite the importance of gates in regulating proteasome function, up to now very few molecules have been shown to interfere with the equilibrium by which the catalytic channel exchanges between the open and closed states. In this light, and inspired by previous results evidencing the antiproteasome potential of cationic porphyrins, here we combine experimental (enzyme kinetics, UV stopped flow and NMR) and computational (bioinformatic analysis and docking studies) approaches to inspect proteasome inhibition by meso-tetrakis(4-N-methylpyridyl)-porphyrin (H2T4) and its two ortho- and meta-isomers. We show that in a first, fast binding event H2T4 accommodates in a pocket made of negatively charged and aromatic residues present in α1 (Asp10, Phe9), α3 (Tyr5), α5 (Asp9, Tyr8), α6 (Asp7, Tyr6) and α7 (Asp9, Tyr8) subunits thereby stabilizing the closed conformation. A second, slower binding mode involves interaction with the grooves which separate the α- from the β-rings. 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