ArticleProceedings of the National Academy of Sciences of the United States of America2013
Structures of a Na+-coupled, substrate-bound MATE multidrug transporter.
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 76 papers.
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Who cites it
76 citing papers in PubMed, 142 citations in OpenAlex.
- The Effect of Famotidine, a MATE1-Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin.Clinical pharmacokinetics · 2016Trial
- Structural basis of drug recognition by human MATE1 transporter.Nature communications · 2025Article
- Prediction of protein structural changes mediated by NS-SNPs in antibiotic resistance determinants in Streptococcus pneumoniae.Archives of microbiology · 2025Article
- Structural insights into a citrate transporter that mediates aluminum tolerance in barley.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structure of WzxE the lipid III flippase for Enterobacterial Common Antigen polysaccharide.Open biology · 2025Article
- The Role of Protonation in the PfMATE Transporter Protein Structural Transitions.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Evaluation of Antibiotic Resistance Mechanisms in Gram-Positive Bacteria.Antibiotics (Basel, Switzerland) · 2024Review
- Rhodamine 19 Alkyl Esters as Effective Antibacterial Agents.International journal of molecular sciences · 2024Article
- Defense mechanisms ofFrontiers in antibiotics · 2024Review
- Antimicrobial Resistance: Two-Component Regulatory Systems and Multidrug Efflux Pumps.Antibiotics (Basel, Switzerland) · 2023Review
- Expression and mutagenesis studies in theFrontiers in plant science · 2023Article
- The culmination of multidrug-resistant efflux pumps vs. meager antibiotic arsenal era: Urgent need for an improved new generation of EPIs.Frontiers in microbiology · 2023Review
- Article
- Structure and Mechanism of the Lipid Flippase MurJ.Annual review of biochemistry · 2022Review
- The Bacterial Cell Wall: From Lipid II Flipping to Polymerization.Chemical reviews · 2022Review
- Understanding paraquat resistance mechanisms in Arabidopsis thaliana to facilitate the development of paraquat-resistant crops.Plant communications · 2022Review
- Membrane Efflux Pumps of PathogenicMicroorganisms · 2022Review
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- The structure of theProceedings of the National Academy of Sciences of the United States of America · 2021Article
- A rice QTL GS3.1 regulates grain size through metabolic-flux distribution between flavonoid and lignin metabolons without affecting stress tolerance.Communications biology · 2021Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Multidrug transporters belonging to the multidrug and toxic compound extrusion (MATE) family expel dissimilar lipophilic and cationic drugs across cell membranes by dissipating a preexisting Na(+) or H(+) gradient. Despite its clinical relevance, the transport mechanism of MATE proteins remains poorly understood, largely owing to a lack of structural information on the substrate-bound transporter. Here we report crystal structures of a Na(+)-coupled MATE transporter NorM from Neisseria gonorrheae in complexes with three distinct translocation substrates (ethidium, rhodamine 6G, and tetraphenylphosphonium), as well as Cs(+) (a Na(+) congener), all captured in extracellular-facing and drug-bound states. The structures revealed a multidrug-binding cavity festooned with four negatively charged amino acids and surprisingly limited hydrophobic moieties, in stark contrast to the general belief that aromatic amino acids play a prominent role in multidrug recognition. Furthermore, we discovered an uncommon cation-π interaction in the Na(+)-binding site located outside the drug-binding cavity and validated the biological relevance of both the substrate- and cation-binding sites by conducting drug resistance and transport assays. Additionally, we uncovered potential rearrangement of at least two transmembrane helices upon Na(+)-induced drug export. Based on our structural and functional analyses, we suggest that Na(+) triggers multidrug extrusion by inducing protein conformational changes rather than by directly competing for the substrate-binding amino acids. This scenario is distinct from the canonical antiport mechanism, in which both substrate and counterion compete for a shared binding site in the transporter. Collectively, our findings provide an important step toward a detailed and mechanistic understanding of multidrug transport.
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Registered trials
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.