Shared structural mechanisms of alternating access between the secondary peptide transporter SbmA and ABC transporters
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
- Hassane El Mkami (ORCID: https://orcid.org/0000-0002-0552-5784)
- Sophia David
- Konstantinos Beis (ORCID: https://orcid.org/0000-0001-5727-4721)
- Satomi Inaba‐Inoue (ORCID: https://orcid.org/0000-0002-6939-1324)
- Anokhi Shah (ORCID: https://orcid.org/0000-0001-9818-5573)
- Chancievan Thangaratnarajah (ORCID: https://orcid.org/0000-0002-0279-6642)
- Thomas Stockner (ORCID: https://orcid.org/0000-0002-7071-8283)
- Piotr Stępień (ORCID: https://orcid.org/0000-0002-4859-6443)
- Amy Clarke (ORCID: https://orcid.org/0009-0006-1319-1311)
- Jonathan G. Heddle (ORCID: https://orcid.org/0000-0003-0994-9928)
- Thijs Ettema
- Norimichi Nomura (ORCID: https://orcid.org/0000-0002-6330-2239)
- Satoshi Ogasawara (ORCID: https://orcid.org/0000-0001-6908-9953)
- Christos Pliotas (ORCID: https://orcid.org/0000-0002-4309-4858)
- Dmitry Ghilarov (ORCID: https://orcid.org/0000-0001-9325-3207)
- Katie Hardman
- Dirk J. Slotboom
- So Iwata (ORCID: https://orcid.org/0000-0003-1735-2937)
- Yue Ma (ORCID: https://orcid.org/0000-0001-5934-0497)
- Leticia Alves da Silva
- Nikas Senning (ORCID: https://orcid.org/0009-0004-5628-0010)
Institutions
- Jagiellonian University (PL)
- Rutherford Appleton Laboratory (GB)
- University of Leeds (GB)
- High Energy Accelerator Research Organization (JP)
- University of St Andrews (GB)
- University of Groningen (NL)
- Durham University (GB)
- Kyoto University (JP)
- University of Manchester (GB)
- University of Oxford (GB)
- Research Complex at Harwell (GB)
- Dialyse Centrum Groningen (NL)
- Granta Design (United Kingdom) (GB)
- Imperial College London (GB)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-15
- DOI
- https://doi.org/10.1038/s41467-026-71633-3
- Citations
- 1
- Primary Topic
- Drug Transport and Resistance Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 15.38
Funders
- Bill and Melinda Gates Foundation
- Japan Agency for Medical Research and Development
- Wellcome Trust
- European Commission
- Rijksuniversiteit Groningen
- Fundacja na rzecz Nauki Polskiej
- Austrian Science Fund
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council
- Japan Society for the Promotion of Science
- European Regional Development Fund