The receptor CRM1 is responsible for the nuclear export of many tumor-suppressor proteins and viral ribonucleoproteins. This renders CRM1 an interesting target for therapeutic intervention in diverse cancer types and viral diseases. Structural studies of Saccharomyces cerevisiae CRM1 (^ScCRM1) complexes with inhibitors defined the molecular basis for CRM1 inhibition. Nevertheless, no structural information is available for inhibitors bound to human CRM1 (^HsCRM1). Here, we present the structure of the natural inhibitor Leptomycin B bound to the ^HsCRM1-RanGTP complex. Despite high sequence conservation and structural similarity in the NES-binding cleft region, ^ScCRM1 exhibits 16-fold lower binding affinity than ^HsCRM1 toward PKI-NES and significant differences in affinities toward potential CRM1 inhibitors. In contrast to ^HsCRM1, competition assays revealed that a human adapted mutant ^ScCRM1-T539C does not bind all inhibitors tested. Taken together, our data indicate the importance of using ^HsCRM1 for molecular analysis and development of novel antitumor and antiviral drugs.

• PMID: 32585100
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Journal Article | Research Support, Non-U.S. Gov't

Authors

Shaikhqasem A, Dickmanns A, Neumann P, Ficner R

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