6tvo
Human CRM1-RanGTP in complex with Leptomycin BHuman CRM1-RanGTP in complex with Leptomycin B
Structural highlights
FunctionXPO1_HUMAN Mediates the nuclear export of cellular proteins (cargos) bearing a leucine-rich nuclear export signal (NES) and of RNAs. In the nucleus, in association with RANBP3, binds cooperatively to the NES on its target protein and to the GTPase RAN in its active GTP-bound form (Ran-GTP). Docking of this complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the cargo from the export receptor. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Involved in U3 snoRNA transport from Cajal bodies to nucleoli. Binds to late precursor U3 snoRNA bearing a TMG cap. Several viruses, among them HIV-1, HTLV-1 and influenza A use it to export their unspliced or incompletely spliced RNAs out of the nucleus. Interacts with, and mediates the nuclear export of HIV-1 Rev and HTLV-1 Rex proteins. Involved in HTLV-1 Rex multimerization.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe 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 ((Sc)CRM1) complexes with inhibitors defined the molecular basis for CRM1 inhibition. Nevertheless, no structural information is available for inhibitors bound to human CRM1 ((Hs)CRM1). Here, we present the structure of the natural inhibitor Leptomycin B bound to the (Hs)CRM1-RanGTP complex. Despite high sequence conservation and structural similarity in the NES-binding cleft region, (Sc)CRM1 exhibits 16-fold lower binding affinity than (Hs)CRM1 toward PKI-NES and significant differences in affinities toward potential CRM1 inhibitors. In contrast to (Hs)CRM1, competition assays revealed that a human adapted mutant (Sc)CRM1-T539C does not bind all inhibitors tested. Taken together, our data indicate the importance of using (Hs)CRM1 for molecular analysis and development of novel antitumor and antiviral drugs. Characterization of Inhibition Reveals Distinctive Properties for Human and Saccharomyces cerevisiae CRM1.,Shaikhqasem A, Dickmanns A, Neumann P, Ficner R J Med Chem. 2020 Jul 23;63(14):7545-7558. doi: 10.1021/acs.jmedchem.0c00143. Epub, 2020 Jul 7. PMID:32585100[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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