ArticleProceedings of the National Academy of Sciences of the United States of America2013
Peptide transporter DtpA has two alternate conformations, one of which is promoted by inhibitor binding.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 27 citations in OpenAlex.
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- The insertase YidC chaperones the polytopic membrane protein MelB inserting and folding simultaneously from both termini.Structure (London, England : 1993) · 2023Article
- Methods to study folding of alpha-helical membrane proteins in lipids.Open biology · 2022Review
- A cholesterol analog stabilizes the human βScience signaling · 2022Article
- Peptide transporter structure reveals binding and action mechanism of a potent PEPT1 and PEPT2 inhibitor.Communications chemistry · 2022Article
- How physical forces drive the process of helical membrane protein folding.EMBO reports · 2022Review
- Membrane Chemistry Tunes the Structure of a Peptide Transporter.Angewandte Chemie (International ed. in English) · 2020Article
- Transcriptional regulator ArcA mediates expression of oligopeptide transport systems both directly and indirectly in Shewanella oneidensis.Scientific reports · 2019Article
- Applications of Single-Molecule Methods to Membrane Protein Folding Studies.Journal of molecular biology · 2018Review
- The non-bilayer lipid MGDG stabilizes the major light-harvesting complex (LHCII) against unfolding.Scientific reports · 2017Article
- YidC assists the stepwise and stochastic folding of membrane proteins.Nature chemical biology · 2016Article
- Molecular Plasticity of the Human Voltage-Dependent Anion Channel Embedded Into a Membrane.Structure (London, England : 1993) · 2016Article
- Impact of holdase chaperones Skp and SurA on the folding of β-barrel outer-membrane proteins.Nature structural & molecular biology · 2015Article
- Observing a lipid-dependent alteration in single lactose permeases.Structure (London, England : 1993) · 2015Article
- Substrate-induced changes in the structural properties of LacY.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
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8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Peptide transporters (PTRs) of the large PTR family facilitate the uptake of di- and tripeptides to provide cells with amino acids for protein synthesis and for metabolic intermediates. Although several PTRs have been structurally and functionally characterized, how drugs modulate peptide transport remains unclear. To obtain insight into this mechanism, we characterize inhibitor binding to the Escherichia coli PTR dipeptide and tripeptide permease A (DtpA), which shows substrate specificities similar to its human homolog hPEPT1. After demonstrating that Lys[Z-NO2]-Val, the strongest inhibitor of hPEPT1, also acts as a high-affinity inhibitor for DtpA, we used single-molecule force spectroscopy to localize the structural segments stabilizing the peptide transporter and investigated which of these structural segments change stability upon inhibitor binding. This characterization was done with DtpA embedded in the lipid membrane and exposed to physiologically relevant conditions. In the unbound state, DtpA adopts two main alternate conformations in which transmembrane α-helix (TMH) 2 is either stabilized (in ∼43% of DtpA molecules) or not (in ∼57% of DtpA molecules). The two conformations are understood to represent the inward- and outward-facing conformational states of the transporter. With increasing inhibitor concentration, the conformation characterized by a stabilized TMH 2 becomes increasingly prevalent, reaching ∼92% at saturation. Our measurements further suggest that Lys[Z-NO2]-Val interacts with discrete residues in TMH 2 that are important for ligand binding and substrate affinity. These interactions in turn stabilize TMH 2, thereby promoting the inhibited conformation of DtpA.
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