Cationic porphyrins are tunable gatekeepers of the 20S proteasome(486 visite)(PDF privato157 visite) Santoro AM, Cunsolo A, D'Urso A, Sbardella D, Tundo GR, Ciaccio C, Coletta M, Diana D, Fattorusso R, Persico M, Di Dato A, Fattorusso C, Milardi D, Purrello R
*** IBB - CNR *** Istituto di Biostrutture e Bioimmagini – CNR UOS di Catania, Via P. Gaifami 18, 95126 Catania, Italy. Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125 Catania, Italy. Dipartimento di Farmacia Università di Napoli “Federico II”, Via D. Montesano, 49 I-80131 Napoli, Italy.
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<span style="font-size: 16px; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">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 </span><span class="italic" style="font-size: 16px; font-style: italic; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">meso</span><span style="font-size: 16px; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">-tetrakis(4-</span><span class="italic" style="font-size: 16px; font-style: italic; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">N</span><span style="font-size: 16px; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">-methylpyridyl)-porphyrin (H</span><small style="font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;"><sub>2</sub></small><span style="font-size: 16px; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">T4) and its two </span><span class="italic" style="font-size: 16px; font-style: italic; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">ortho</span><span style="font-size: 16px; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">- and </span><span class="italic" style="font-size: 16px; font-style: italic; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">meta</span><span style="font-size: 16px; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">-isomers. We show that in a first, fast binding event H</span><small style="font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;"><sub>2</sub></small><span style="font-size: 16px; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">T4 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. Of note, the proteasome inhibition by </span><span class="italic" style="font-size: 16px; font-style: italic; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">ortho</span><span style="font-size: 16px; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">- and </span><span class="italic" style="font-size: 16px; font-style: italic; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">meta</span><span style="font-size: 16px; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">-H</span><small style="font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;"><sub>2</sub></small><span style="font-size: 16px; font-family: 'Times New Roman', Helvetica, sans-serif; line-height: 24px;">T4 decreases significantly if compared to the parent compound, thus underscoring the role played by spatial distribution of the four peripheral positive charges in regulating proteasome–ligand interactions. We think that our results may pave the way to further studies aimed at rationalizing the molecular basis of novel, and more sophisticated, proteasome regulatory mechanisms.</span>
93 Records (92 escludendo Abstract e Conferenze). Impact factor totale: 397.266 (393.536 escludendo Abstract e Conferenze). Impact factor a 5 anni totale: 415.903 (412.939 escludendo Abstract e Conferenze).
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