Structural basis for polyspecificity in the POT family of proton-coupled oligopeptide transporters



An enigma in the field of peptide transport is the structural basis for ligand promiscuity, as exemplified by PepT1, the mammalian plasma membrane peptide transporter. Here, we present crystal structures of di- and tripeptide-bound complexes of a bacterial homologue of PepT1, which reveal at least two mechanisms for peptide recognition that operate within a single, centrally located binding site. The dipeptide was orientated laterally in the binding site, whereas the tripeptide revealed an alternative vertical binding mode. The co-crystal structures combined with functional studies reveal that biochemically distinct peptide-binding sites likely operate within the POT/PTR family of proton-coupled symporters and suggest that transport promiscuity has arisen in part through the ability of the binding site to accommodate peptides in multiple orientations for transport.



Mammalian members of the POT family transport both di- and tripeptides. This study shows that a bacterial member of this family is able to recognize di- and tripeptides in different orientations, explaining this remarkable ligand promiscuity.

  • Crystal structures of a POT transporter bound by di- and tripeptides.
  • Structural and biochemical data support alternative binding modes for these peptides.