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High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
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SINE compounds activate exportin-1 degradation via an allosteric mechanism
Biorxiv : the Preprint Server for Biology
|October 17, 2024
Summary
Selinexor and KPT-185 are cancer drugs that target Exportin 1 (XPO1) degradation. New structures reveal these drugs act as allosteric degraders, stabilizing XPO1 for degradation by the CRL5ASB8 system.
Area of Science:
- Molecular biology
- Structural biology
- Cancer research
Background:
- Exportin 1 (XPO1/CRM1) overexpression in cancer disrupts protein localization.
- XPO1 inhibitors like selinexor restore cargo localization by targeting XPO1 for degradation.
Purpose of the Study:
- To elucidate the mechanism of XPO1 inhibition and degradation by selinexor/KPT-185 via the CRL5ASB8 system.
- To determine the structural basis for inhibitor-XPO1 engagement and subsequent ubiquitination.
Main Methods:
- Cryogenic electron microscopy (cryo-EM) to determine high-resolution structures.
- Biochemical assays to assess protein-ligand interactions and ubiquitination.
Main Results:
- Cryo-EM structures reveal ASB8 binding to a unique drug-induced degron on XPO1.
- Selinexor/KPT-185 binding significantly increases XPO1-ASB8 affinity, promoting CRL5ASB8-mediated ubiquitination.
- The mechanism is allosteric, with drugs binding XPO1 to stabilize an ASB8-binding conformation, distinct from molecular glues.
Conclusions:
- Selinexor/KPT-185 function as allosteric degraders, not molecular glues.
- This expands the understanding of targeted protein degradation mechanisms via the CRL5 system.
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