The importance of allosteric proteasome inhibition in the treatment of cancer is becoming increasingly evident. Motivated by this urgent therapeutic need, we have recently identified cationic porphyrins as a highly versatile class of molecules able to regulate proteasome activity by interfering with gating mechanisms. In the present study, the mapping of electrostatic contacts bridging the regulatory particles with the α-rings of the human 20S proteasome led us to the identification of (meso-tetrakis(4-N-methylphenyl pyridyl)-porphyrin (pTMPyPP4) as a novel non-competitive inhibitor of human 20S proteasome. pTMPyPP4 inhibition mechanism implies a positive cooperative binding to proteasome, which disappears when a permanently open proteasome mutant (α-3ΔN) is used, supporting the hypothesis that the events associated with allosteric proteasome inhibition by pTMPyPP4 interfere with 20S gating and affect its "open-closed" equilibrium. Therefore, we propose that the spatial distribution of the negatively charged residues responsible for the interaction with regulatory particles at the α-ring surface of human 20S may be exploited as a blueprint for the design of allosteric proteasome regulators. © 2017 The Author(s).

Dato, A.d., Cunsolo, A., Persico, M., Santoro, A.m., D'Urso, A., Milardi, D., et al. (2017). Electrostatic Map of Proteasome α-Rings Encodes the Design of Allosteric Porphyrin-Based Inhibitors Able to Affect 20S Conformation by Cooperative Binding. SCIENTIFIC REPORTS, 7(1) [10.1038/s41598-017-17008-7].

Electrostatic Map of Proteasome α-Rings Encodes the Design of Allosteric Porphyrin-Based Inhibitors Able to Affect 20S Conformation by Cooperative Binding

Persico M.;Stefanelli M.;Paolesse R.;Tundo G. R.;Sbardella D.;Coletta M.
2017-01-01

Abstract

The importance of allosteric proteasome inhibition in the treatment of cancer is becoming increasingly evident. Motivated by this urgent therapeutic need, we have recently identified cationic porphyrins as a highly versatile class of molecules able to regulate proteasome activity by interfering with gating mechanisms. In the present study, the mapping of electrostatic contacts bridging the regulatory particles with the α-rings of the human 20S proteasome led us to the identification of (meso-tetrakis(4-N-methylphenyl pyridyl)-porphyrin (pTMPyPP4) as a novel non-competitive inhibitor of human 20S proteasome. pTMPyPP4 inhibition mechanism implies a positive cooperative binding to proteasome, which disappears when a permanently open proteasome mutant (α-3ΔN) is used, supporting the hypothesis that the events associated with allosteric proteasome inhibition by pTMPyPP4 interfere with 20S gating and affect its "open-closed" equilibrium. Therefore, we propose that the spatial distribution of the negatively charged residues responsible for the interaction with regulatory particles at the α-ring surface of human 20S may be exploited as a blueprint for the design of allosteric proteasome regulators. © 2017 The Author(s).
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Rilevanza internazionale
Articolo
Esperti anonimi
Settore CHIM/07 - Fondamenti Chimici delle Tecnologie
Settore CHIM/03 - Chimica Generale e Inorganica
Settore BIO/10
English
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https://www.scopus.com/inward/record.uri?eid=2-s2.0-85038018147&doi=10.1038%2fs41598-017-17008-7&partnerID=40&md5=bf023a209bca87556221d41499da324a
Dato, A.d., Cunsolo, A., Persico, M., Santoro, A.m., D'Urso, A., Milardi, D., et al. (2017). Electrostatic Map of Proteasome α-Rings Encodes the Design of Allosteric Porphyrin-Based Inhibitors Able to Affect 20S Conformation by Cooperative Binding. SCIENTIFIC REPORTS, 7(1) [10.1038/s41598-017-17008-7].
Dato, Ad; Cunsolo, A; Persico, M; Santoro, Am; D'Urso, A; Milardi, D; Purrello, R; Stefanelli, M; Paolesse, R; Tundo, Gr; Sbardella, D; Fattorusso, C; Coletta, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/193375
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