ArticleProceedings of the National Academy of Sciences of the United States of America2022
Integrated AlphaFold2 and DEER investigation of the conformational dynamics of a pH-dependent APC antiporter.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 37 citations in OpenAlex.
- Protocol for preparing and characterizing samples for combined microsecond freeze-hyperquenching and electron paramagnetic resonance spectroscopy.STAR protocols · 2026Article
- Structural bases of signal generation and transduction by the SPS amino acid sensor of Saccharomyces cerevisiae.G3 (Bethesda, Md.) · 2026Article
- Insight into Malt1 activation mechanism through synergetic approach of AlphaFold, MD Simulation and NMR dynamic analyses.bioRxiv : the preprint server for biology · 2025Article
- Recent advances in quantifying protein conformational ensembles with dipolar EPR spectroscopy.Current opinion in structural biology · 2025Review
- Accurate Protein Dynamic Conformational Ensembles: Combining AlphaFold, MD, and AmideInternational journal of molecular sciences · 2025Article
- Resurgence of magnetic resonance techniques in the era of AlphaFold.Biophysical reviews · 2025Review
- Protein Modeling with DEER Spectroscopy.Annual review of biophysics · 2025Review
- Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.Science advances · 2025Article
- Conformations of influenza A M2 protein in DOPC/DOPS and E. coli native lipids and proteins.Biophysical journal · 2024Article
- Insights into mechanisms of MALT1 allostery from NMR and AlphaFold dynamic analyses.Communications biology · 2024Article
- Deep learning for protein structure prediction and design-progress and applications.Molecular systems biology · 2024Review
- A comparative study of influenza A M2 protein conformations in DOPC/DOPS liposomes and in nativebioRxiv : the preprint server for biology · 2024Article
- A DNA unwinding equilibrium serves as a checkpoint for CRISPR-Cas12a target discrimination.Nucleic acids research · 2023Article
- Darobactin B Stabilises a Lateral-Closed Conformation of the BAM Complex in E. coli Cells.Angewandte Chemie (International ed. in English) · 2023Article
- Darobactin B Stabilises a Lateral-Closed Conformation of the BAM Complex inAngewandte Chemie (Weinheim an der Bergstrasse, Germany) · 2023Article
- Two putative glutamate decarboxylases of Streptococcus pneumoniae as possible antigens for the production of anti-GAD65 antibodies leading to type 1 diabetes mellitus.International microbiology : the official journal of the Spanish Society for Microbiology · 2023Article
- A novel approach to modeling side chain ensembles of the bifunctional spin label RX.bioRxiv : the preprint server for biology · 2023Article
- Exploring and Learning the Universe of Protein Allostery Using Artificial Intelligence Augmented Biophysical and Computational Approaches.Journal of chemical information and modeling · 2023Review
- chiLife: An open-source Python package for in silico spin labeling and integrative protein modeling.PLoS computational biology · 2023Article
- Targeting in silico GPCR conformations with ultra-large library screening for hit discovery.Trends in pharmacological sciences · 2023Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 2 countries.
Funding
Abstract
The Amino Acid-Polyamine-Organocation (APC) transporter GadC contributes to the survival of pathogenic bacteria under extreme acid stress by exchanging extracellular glutamate for intracellular γ-aminobutyric acid (GABA). Its structure, determined in an inward-facing conformation at alkaline pH, consists of the canonical LeuT-fold with a conserved five-helix inverted repeat, thereby resembling functionally divergent transporters such as the serotonin transporter SERT and the glucose-sodium symporter SGLT1. However, despite this structural similarity, it is unclear if the conformational dynamics of antiporters such as GadC follow the blueprint of these or other LeuT-fold transporters. Here, we used double electron-electron resonance (DEER) spectroscopy to monitor the conformational dynamics of GadC in lipid bilayers in response to acidification and substrate binding. To guide experimental design and facilitate the interpretation of the DEER data, we generated an ensemble of structural models in multiple conformations using a recently introduced modification of AlphaFold2 . Our experimental results reveal acid-induced conformational changes that dislodge the Cterminus from the permeation pathway coupled with rearrangement of helices that enables isomerization between inward- and outward-facing states. The substrate glutamate, but not GABA, modulates the dynamics of an extracellular thin gate without shifting the equilibrium between inward- and outward-facing conformations. In addition to introducing an integrated methodology for probing transporter conformational dynamics, the congruence of the DEER data with patterns of structural rearrangements deduced from ensembles of AlphaFold2 models illuminates the conformational cycle of GadC underpinning transport and exposes yet another example of the divergence between the dynamics of different families in the LeuT-fold.
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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.