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Characterization of Inhibition Reveals Distinctive Properties for Human and Saccharomyces cerevisiae CRM1.
Shaikhqasem, Alaa; Dickmanns, Achim; Neumann, Piotr; Ficner, Ralf.
Afiliación
  • Shaikhqasem A; Department of Molecular Structural Biology, Institute of Microbiology and Genetics, GZMB, Georg-August-University Göttingen, 37077 Göttingen, Germany.
  • Dickmanns A; Department of Molecular Structural Biology, Institute of Microbiology and Genetics, GZMB, Georg-August-University Göttingen, 37077 Göttingen, Germany.
  • Neumann P; Department of Molecular Structural Biology, Institute of Microbiology and Genetics, GZMB, Georg-August-University Göttingen, 37077 Göttingen, Germany.
  • Ficner R; Department of Molecular Structural Biology, Institute of Microbiology and Genetics, GZMB, Georg-August-University Göttingen, 37077 Göttingen, Germany.
J Med Chem ; 63(14): 7545-7558, 2020 07 23.
Article en En | MEDLINE | ID: mdl-32585100
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Citoplasmáticos y Nucleares / Carioferinas / Proteínas de Saccharomyces cerevisiae Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Citoplasmáticos y Nucleares / Carioferinas / Proteínas de Saccharomyces cerevisiae Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos