Structural mechanism of 26S proteasome regulation and its pharmacological modulation

The proteasome is a conserved proteolytic machinery that maintains protein quality control and regulates nearly every aspect of cellular activities. It is a clinically validated therapeutic target in cancer and holds great potential in therapeutic discovery for protein aggregation-associated disorders. Advances in structural biology have elucidated the architecture and conformational dynamics of the 26S proteasome, providing mechanistic insights into substrate recognition, unfolding, translocation, and proteolysis by the proteasome and pharmacological intervention. This review article summarizes current knowledge on the structural basis of substrate processing by the 26S proteasome and highlights emerging regulatory mechanisms mediated by enzymatic cofactors. We outline the molecular principles underlying current inhibitors and activators targeting various components of the proteasome, as well as targeted-degradation strategies directly involving the proteasome. We further discuss how new views of proteasome dynamics and allosteric regulation by protein cofactors and small molecules may shape the rational design of next-generation proteasome modulators with broadened therapeutic applications.