No abstract

Mechanosensitive nuclear pores The nucleus of eukaryotic cells is enclosed by the nuclear envelope, a double membrane punctuated with nuclear pore complexes (NPCs). These giant channels in the nuclear envelope mediate nucleocytoplasmic exchange. Zimmerli et al . show that the mechanical status of the nuclear membranes controls their nuclear pore diameter. Pulling forces imposed through nuclear membranes lead to stretching of NPCs and dilation of their diameter, whereas relief of such forces causes NPC constriction. Thus, the control of nuclear size and shape is functionally linked with NPC conformation and nucleocytoplasmic transport activity. —SMH

Members of the solute carrier 15 family (SLC15) transport di- and tripeptides as well as peptidomimetic drugs across the cell membrane. Structures of bacterial homologues have provided valuable information on the binding and transport of their natural substrates, but many do not transport medically relevant drugs. In contrast, a homologue from Escherichia coli, DtpA (dipeptide and tripeptide permease), shows a high similarity to human PepT1 (SLC15A1) in terms of ligand selectivity and transports a similar set of drugs. Here, we present the crystal structure of DtpA in ligand-free form (at 3.30 Å resolution) and in complex with the antiviral prodrug valganciclovir (at 2.65 Å resolution) supported by biochemical data. We show that valganciclovir unexpectedly binds with the ganciclovir moiety mimicking the N-terminal residue of a canonical peptide substrate. On the basis of a homology model we argue that this binding mode also applies to the human PepT1 transporter. Our results provide new insights into the binding mode of prodrugs and will assist the rational design of drugs with improved absorption rates.