Pitstop-2 Upsets The Integrity of Nuclear Pore Complexes (NPCs) by Interaction with ß-Propeller Folds of Npc Scaffold Proteins.
Adv Biol (Weinh)
; 8(3): e2300360, 2024 03.
Article
em En
| MEDLINE
| ID: mdl-38129324
ABSTRACT
The small compound Pitstop-2 is a recent potent inhibitor of clathrin-mediated endocytosis (CME), widely used in biomedical research areas. In recent years, however, it is observed that it exhibits CME-independent inhibitory effects on nuclear pore complexes (NPCs), the nucleocytoplasmic gatekeepers. NPCs are elaborate proteinaceous transport nano-machineries of crucial physiological importance rendering them novel targets for various medical applications. They mediate all nucleocytoplasmic transport forming a physiologically essential selective nucleocytoplasmic barrier. The direct Pitstop-2 disruptive effects on NPCs manifested themselves at both the structural and functional integrity levels. Moreover, they are massive, acute, and detectable at concentrations equal to CME-inhibitory concentrations. Pitstop-2 inhibits CME by binding to the terminal ß-propeller domain of the heavy chain of clathrin. Several NPC scaffold proteins, critical for the structural and functional integrity of the NPC, possess ß-propeller folds. Herein, utilizing computational docking analysis, it is demonstrated that Pitstop-2 exhibits particularly high binding affinities to ß-propeller folds of NPC scaffold proteins, similar to its binding affinity to the terminal ß-propeller domain of clathrin. The authors, therefore, conclude that Pitstop-2 is a potent disruptor of NPCs, an activity which, separately or in synergy with CME inhibition, may be exploited for a myriad of pharmacological applications.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Poro Nuclear
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Pesquisa Biomédica
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Tiazolidinas
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article