Abstract
Protein-protein interactions (PPI) are at the center of molecular mechanisms of life. The protein ligands convene for regulation of biological function: adding, enhancing or inhibiting activity, for assistance in structural integrity or to enable subsequent PPI. All these general roles of PPI are represented in the proteasome, the giant proteolytic factory universally present in human cells. The proteasome is a renowned target for anti-cancer drugs and a considered target for drugs curbing inflammation. The essential function of the proteasome, the degradation of a majority of intracellular proteins via the ubiquitin-proteasome pathway, relies on proper interactions between multiple subunits of the enzyme and between multiple modules forming distinct super-assemblies covered by the “proteasome” name. The interface regions between constitutive, alternative or transient protein components of the proteasome provide a rich platform for design of drugs with potentially very diverse actions. Still, the resource remains largely untapped since all proteasometargeting drugs used so far in humans are classical competitive inhibitors blocking catalytic centers. In this review, we will discuss the opportunities and challenges of targeting PPI in the hub enzyme for intracellular protein catabolism, the proteasome.
Keywords: Allostery, Cancer, Drugs, Inhibitors, Proteasome, Protein-protein interactions, Proteolysis, Ubiquitin-proteasome pathway.
Current Topics in Medicinal Chemistry
Title:Targeting Protein-Protein Interactions in the Proteasome Super-Assemblies.
Volume: 15 Issue: 20
Author(s): Maria Gaczynska and Pawel A. Osmulski
Affiliation:
Keywords: Allostery, Cancer, Drugs, Inhibitors, Proteasome, Protein-protein interactions, Proteolysis, Ubiquitin-proteasome pathway.
Abstract: Protein-protein interactions (PPI) are at the center of molecular mechanisms of life. The protein ligands convene for regulation of biological function: adding, enhancing or inhibiting activity, for assistance in structural integrity or to enable subsequent PPI. All these general roles of PPI are represented in the proteasome, the giant proteolytic factory universally present in human cells. The proteasome is a renowned target for anti-cancer drugs and a considered target for drugs curbing inflammation. The essential function of the proteasome, the degradation of a majority of intracellular proteins via the ubiquitin-proteasome pathway, relies on proper interactions between multiple subunits of the enzyme and between multiple modules forming distinct super-assemblies covered by the “proteasome” name. The interface regions between constitutive, alternative or transient protein components of the proteasome provide a rich platform for design of drugs with potentially very diverse actions. Still, the resource remains largely untapped since all proteasometargeting drugs used so far in humans are classical competitive inhibitors blocking catalytic centers. In this review, we will discuss the opportunities and challenges of targeting PPI in the hub enzyme for intracellular protein catabolism, the proteasome.
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Cite this article as:
Gaczynska Maria and Osmulski A. Pawel, Targeting Protein-Protein Interactions in the Proteasome Super-Assemblies., Current Topics in Medicinal Chemistry 2015; 15 (20) . https://dx.doi.org/10.2174/1568026615666150519103206
DOI https://dx.doi.org/10.2174/1568026615666150519103206 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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