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.
Pain remained a problem despite the pre-emptive use of opioids, non-steroidal anti-inflammatory drugs and local anaesthesia, irrespective of surgical technique.
Does freezing of sensory nerves in the groin reduce pain after hernia repair? Extreme cold (-60 degrees C) was applied in a double-blind, randomized study. No difference in pain scores was found. Sensory disturbances were seen in treatment and control patients. Freezing cannot be recommended for pain relief after hernia repair.
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