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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.

Original publication

DOI

10.15252/embr.201338403

Type

Journal article

Journal

EMBO Rep

Publication Date

08/2014

Volume

15

Pages

886 - 893

Keywords

POT/PTR family, crystallography, major facilitator superfamily, membrane protein, peptide binding site, Bacterial Proteins, Binding Sites, Crystallography, X-Ray, Dipeptides, Hydrogen Bonding, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Oligopeptides, Protein Structure, Secondary, Streptococcus thermophilus, Substrate Specificity, Symporters