ArticleProceedings of the National Academy of Sciences of the United States of America2011
Evidence for an allosteric mechanism of substrate release from membrane-transporter accessory binding proteins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 40 citations in OpenAlex.
- Optimizing Stability in Dynamic Small-Molecule Binding Proteins.Journal of the American Chemical Society · 2026Article
- On the function of TRAP substrate-binding proteins: the isethionate-specific binding protein IseP.The Biochemical journal · 2024Article
- Allosteric substrate release by a sialic acid TRAP transporter substrate binding protein.Communications biology · 2024Article
- Conformational free-energy landscapes of a NaProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Structural and mechanistic analysis of a tripartite ATP-independent periplasmic TRAP transporter.Nature communications · 2022Article
- Selective Nutrient Transport in Bacteria: Multicomponent Transporter Systems Reign Supreme.Frontiers in molecular biosciences · 2021Review
- Interpreting Hydrogen-Deuterium Exchange Experiments with Molecular Simulations: Tutorials and Applications of the HDXer Ensemble Reweighting Software [Article v1.0].Living journal of computational molecular science · 2021Article
- Interpretation of HDX Data by Maximum-Entropy Reweighting of Simulated Structural Ensembles.Biophysical journal · 2020Article
- Structure functional insights into calcium binding during the activation of coagulation factor XIII A.Scientific reports · 2019Article
- Structural Characterization of Biomolecules through Atomistic Simulations Guided by DEER Measurements.Structure (London, England : 1993) · 2019Article
- Differential Substrate Recognition by Maltose Binding Proteins Influenced by Structure and Dynamics.Biochemistry · 2018Article
- Confidence Analysis of DEER Data and Its Structural Interpretation with Ensemble-Biased Metadynamics.Biophysical journal · 2018Article
- PELDOR Spectroscopy Reveals Two Defined States of a Sialic Acid TRAP Transporter SBP in Solution.Biophysical journal · 2017Article
- Channeling your inner energy.Nature structural & molecular biology · 2014Article
- P-loop conformation governed crizotinib resistance in G2032R-mutated ROS1 tyrosine kinase: clues from free energy landscape.PLoS computational biology · 2014Article
- Two-state dynamics of the SH3-SH2 tandem of Abl kinase and the allosteric role of the N-cap.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Numerous membrane importers rely on accessory water-soluble proteins to capture their substrates. These substrate-binding proteins (SBP) have a strong affinity for their ligands; yet, substrate release onto the low-affinity membrane transporter must occur for uptake to proceed. It is generally accepted that release is facilitated by the association of SBP and transporter, upon which the SBP adopts a conformation similar to the unliganded state, whose affinity is sufficiently reduced. Despite the appeal of this mechanism, however, direct supporting evidence is lacking. Here, we use experimental and theoretical methods to demonstrate that an allosteric mechanism of enhanced substrate release is indeed plausible. First, we report the atomic-resolution structure of apo TeaA, the SBP of the Na(+)-coupled ectoine TRAP transporter TeaBC from Halomonas elongata DSM2581(T), and compare it with the substrate-bound structure previously reported. Conformational free-energy landscape calculations based upon molecular dynamics simulations are then used to dissect the mechanism that couples ectoine binding to structural change in TeaA. These insights allow us to design a triple mutation that biases TeaA toward apo-like conformations without directly perturbing the binding cleft, thus mimicking the influence of the membrane transporter. Calorimetric measurements demonstrate that the ectoine affinity of the conformationally biased triple mutant is 100-fold weaker than that of the wild type. By contrast, a control mutant predicted to be conformationally unbiased displays wild-type affinity. This work thus demonstrates that substrate release from SBPs onto their membrane transporters can be facilitated by the latter through a mechanism of allosteric modulation of the former.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.