Recent advances in structural biology of peptide transporters

Peptide transporters localized at brush-border membranes of intestinal and renal epithelial cells mediate the membrane transport of di- and tripeptides, and play important roles in protein absorption and the conservation of peptide-bound amino nitrogen. Peptide-like drugs that show structural similarities to di- and tripeptides are also recognized by peptide transporters. The energy for transport of small peptides and peptide-like drugs is provided by the proton gradient across the cell membrane. Since the cloning of H(+)/peptide cotransporter (PEPT1, SLC15A1), there have been advances in the molecular biology, biochemistry, biophysics and structural determination of PEPT1. By integrating these advances, much effort has been made to understand the relationship between structure and function. In silico experimental strategies are classified as (1) construction of kinetic models, (2) computer modeling of PEPT1 structure and (3) homology modeling of PEPT1 with crystal structures of bacterial transporters. The hypotheses regarding the structure-function relationship produced by these strategies have been confirmed by in vitro mutagenesis including cysteine-scanning mutagenesis. Recently, the crystal structure of PepT(So), a functionally similar prokaryotic homolog of the mammalian peptide transporters from Shewanella oneidensis, was classified, and the previous hypotheses regarding the structure-function relationship of PEPT1 have been re-evaluated. This review highlights the recent advances in our knowledge of the structural biology of PEPT1.