Atomic basis of CRM1-cargo recognition, release and inhibition
Ho Yee Joyce Fung1, Yuh Min Chook1
1Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park, Dallas, TX 75390-9041, USA.
Abstract:
CRM1 or XPO1 is the major nuclear export receptor in the cell, which controls the nuclear-cytoplasmic localization of many proteins and RNAs. CRM1 is also a promising cancer drug target as the transport receptor is overexpressed in many cancers where some of its cargos are misregulated and mislocalized to the cytoplasm. Atomic level understanding of CRM1 function has greatly facilitated recent drug discovery and development of CRM1 inhibitors to target a variety of malignancies. Numerous atomic resolution CRM1 structures are now available, explaining how the exporter recognizes nuclear export signals in its cargos, how RanGTP and cargo bind with positive cooperativity, how RanBP1 causes release of export cargos in the cytoplasm and how diverse inhibitors such as Leptomycin B and the new KPT-SINE compounds block nuclear export. This review summarizes structure-function studies that explain CRM1-cargo recognition, release and inhibition.
Insights
CRM1 (XPO1) is a key protein export receptor overexpressed in cancer. Understanding its atomic structure reveals how it binds cargo and how inhibitors block this process, aiding cancer drug development.
Area of Science:
- Molecular Biology
- Structural Biology
- Oncology
Background:
- CRM1 (XPO1) is the primary nuclear export receptor, regulating protein and RNA localization.
- CRM1 is overexpressed in many cancers, leading to cargo mislocalization and contributing to malignancy.
- Atomic-level structural insights into CRM1 function are crucial for developing targeted cancer therapies.
Purpose of the Study:
- To review structure-function studies of CRM1 (XPO1).
- To explain CRM1-cargo recognition, binding mechanisms, and cargo release.
- To summarize how CRM1 inhibitors block nuclear export.
Main Methods:
- Analysis of atomic resolution CRM1 structures.
- Review of structure-function relationship studies.
- Examination of CRM1 inhibitor mechanisms.
Main Results:
- Detailed understanding of CRM1's recognition of nuclear export signals.
- Elucidation of the cooperative binding of RanGTP and cargo.
- Explanation of RanBP1's role in cytoplasmic cargo release.
- Characterization of inhibition mechanisms by Leptomycin B and KPT-SINE compounds.
Conclusions:
- Atomic structures of CRM1 provide critical insights into its transport functions.
- Understanding CRM1 structure-function relationships facilitates the development of novel cancer therapeutics.
- CRM1 remains a promising target for the treatment of various malignancies.
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