biostudies-literaturePersico MItalian Ministry of University and Research741https://www.ebi.ac.uk/biostudies/studies/S-EPMC9220251biostudies-literatureUnknown12(6)Cationic porphyrins exhibit an amazing variety of binding modes and inhibition mechanisms of 20S proteasome. Depending on the spatial distribution of their electrostatic charges, they can occupy different sites on α rings of 20S proteasome by exploiting the structural code responsible for the interaction with regulatory proteins. Indeed, they can act as competitive or allosteric inhibitors by binding at the substrate gate or at the grooves between the α subunits, respectively. Moreover, the substitution of a charged moiety in the peripheral arm with a hydrophobic moiety revealed a "new" 20S functional state with higher substrate affinity and catalytic efficiency. In the present study, we expand our structure-activity relationship (SAR) analysis in order to further explore the potential of BiomoleculesModulation of the 20S Proteasome Activity by Porphyrin Derivatives Is Steered through Their Charge Distribution.PMC92202512017YJMPZN -005Sbardella DSantoro AMGobbo MPurrello RFattorusso CMilardi DDiana DCunsolo AFattorusso RStefanelli MD'Urso ATundo GRColetta MPersico MfalseModulation of the 20S Proteasome Activity by Porphyrin Derivatives Is Steered through Their Charge Distribution.Cationic porphyrins exhibit an amazing variety of binding modes and inhibition mechanisms of 20S proteasome. Depending on the spatial distribution of their electrostatic charges, they can occupy different sites on α rings of 20S proteasome by exploiting the structural code responsible for the interaction with regulatory proteins. Indeed, they can act as competitive or allosteric inhibitors by binding at the substrate gate or at the grooves between the α subunits, respectively. Moreover, the substitution of a charged moiety in the peripheral arm with a hydrophobic moiety revealed a "new" 20S functional state with higher substrate affinity and catalytic efficiency. In the present study, we expand our structure-activity relationship (SAR) analysis in order to further explore the potential of 2022-01-01T00:00:00Z2022 May2026-05-06T03:08:49.196Z2025-05-18T12:04:57.943ZS-EPMC92202513574086510.3390/biom12060741