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Characterization of Inhibition Reveals Distinctive Properties for Human and Saccharomyces cerevisiae CRM1

Alaa Shaikhqasem1, Achim Dickmanns1, Piotr Neumann1

  • 1Department of Molecular Structural Biology, Institute of Microbiology and Genetics, GZMB, Georg-August-University Göttingen, 37077 Göttingen, Germany.

Journal of Medicinal Chemistry
|June 26, 2020
PubMed

Insights

Human CRM1 (exportin 1) is crucial for cancer and viral diseases. We determined the structure of human CRM1 bound to Leptomycin B, revealing key differences from yeast CRM1 for drug development.

Area of Science:

  • Molecular biology
  • Structural biology
  • Biochemistry

Background:

  • CRM1 (exportin 1) mediates nuclear export of tumor suppressors and viral RNAs.
  • CRM1 is a therapeutic target for cancer and viral infections.
  • Previous structural studies focused on yeast CRM1, not human CRM1.

Purpose of the Study:

  • To determine the structure of human CRM1 bound to the natural inhibitor Leptomycin B.
  • To compare the binding affinities of inhibitors to human CRM1 versus yeast CRM1.
  • To guide the development of novel CRM1-targeting drugs.

Main Methods:

  • X-ray crystallography of the human CRM1-RanGTP-Leptomycin B complex.
  • Inhibitor competition binding assays.
  • Site-directed mutagenesis of human CRM1.

Main Results:

  • The structure of human CRM1 bound to Leptomycin B was elucidated.
  • Human CRM1 showed significantly lower binding affinity for certain inhibitors compared to yeast CRM1.
  • A human-adapted CRM1 mutant (T539C) displayed altered inhibitor binding profiles.

Conclusions:

  • Structural and binding differences exist between human and yeast CRM1.
  • Human CRM1 is essential for accurate molecular analysis and drug development.
  • Targeting human CRM1 offers potential for new anticancer and antiviral therapies.

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