Shared structural mechanisms of alternating access between the secondary peptide transporter SbmA and ABC transporters

Journal article

SbmA is a membrane transporter from Escherichia coli that imports antimicrobial peptides. SbmA belongs to the SbmA-like peptide transporter (SLiPT) family. Although the protein is a secondary active transporter that is energized by the proton gradient, it is structurally related to the transmembrane domain (TMD) of ATP-binding cassette (ABC) transporters. SbmA therefore bridges the structural divide between primary and secondary transporters. However, it remains unclear, if SbmA also shares the mechanism of alternating access with ABC transporters, because only a single (outward-open) state is resolved. Here, we show by sequence analysis that SbmA is likely evolved from the TMD of an early ancestor of the ABC transporter YddA. We determine the cryogenic electron microscopy structures of SbmA in occluded and inward-facing states. These conformations closely resemble equivalent states found in ABC transporters, indicating a shared structural mechanism of transport. In contrast to ABC transporters, where nucleotide binding, hydrolysis and release steer conformational changes necessary for substrate translocation, electron paramagnetic resonance (EPR) spectroscopy and molecular dynamics (MD) simulations reveal how pH changes induce conformational transitions in SbmA, consistent with a mechanism of substrate internalization that utilizes the transmembrane proton gradient.

Authors: Ettema, TW; Inaba-Inoue, S; Thangaratnarajah, C; Alves da Silva, L; Senning, N

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Publication date: 2026-04-15
• Acceptance date: 2026-03-21
• DOI: 10.1038/s41467-026-71633-3
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Transmembrane protein; Transporter; Transmembrane domain; Cyclic nucleotide-binding domain; ATP-binding cassette transporter; Protein structure; Protein secondary structure; Peptide