Journal
EMBO JOURNAL
Volume 30, Issue 2, Pages 417-426Publisher
WILEY
DOI: 10.1038/emboj.2010.309
Keywords
major facilitator superfamily transporter; occluded state; peptide transport
Categories
Funding
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Membrane Protein Structure Initiative (MPSi) [BBS/B/14418]
- Wellcome Trust [062164/Z/00/Z]
- Japan Science and Technology Agency
- Medical Research Council
- Royal Society
- MEXT, Japan
- BBSRC [BB/G023425/1] Funding Source: UKRI
- MRC [G0900399] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/B/14418, BB/G023425/1] Funding Source: researchfish
- Medical Research Council [G0900399] Funding Source: researchfish
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PepT1 and PepT2 are major facilitator superfamily (MFS) transporters that utilize a proton gradient to drive the uptake of di- and tri-peptides in the small intestine and kidney, respectively. They are the major routes by which we absorb dietary nitrogen and many orally administered drugs. Here, we present the crystal structure of PepT(So), a functionally similar prokaryotic homologue of the mammalian peptide transporters from Shewanella oneidensis. This structure, refined using data up to 3.6 angstrom resolution, reveals a ligand-bound occluded state for the MFS and provides new insights into a general transport mechanism. We have located the peptide-binding site in a central hydrophilic cavity, which occludes a bound ligand from both sides of the membrane. Residues thought to be involved in proton coupling have also been identified near the extracellular gate of the cavity. Based on these findings and associated kinetic data, we propose that PepT(So) represents a sound model system for understanding mammalian peptide transport as catalysed by PepT1 and PepT2. The EMBO Journal (2011) 30, 417-426. doi:10.1038/emboj.2010.309; Published online 3 December 2010
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