ArticleNature chemical biology2023
Deep mutational scan of a drug efflux pump reveals its structure-function landscape.
Article in Nature chemical biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
What it found
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Who cites it
29 citing papers in PubMed, 50 citations in OpenAlex.
- Sequence Display enables large-scale sequence-activity datasets for rapid protein evolution.Nature biotechnology · 2026Article
- Determinants of metal import and specificity in a bacterial transporter.bioRxiv : the preprint server for biology · 2026Article
- Structural basis of lipid-linked galactan export by the mycobacterial ABC transporter Wzm-Wzt.Nature communications · 2026Article
- D-LIM: A neural network for interpretable gene-gene interactions.PLoS computational biology · 2026Article
- Antibody-enabled structural biology and AI-driven antibody design.Frontiers in pharmacology · 2026Review
- Covalently constrained 'Di-Gembodies' enable parallel structure solutions by cryo-EM.Nature chemical biology · 2026Article
- Energetic and structural control of polyspecificity in a multidrug transporter.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Identification and understanding of allostery hotspots in proteins: Integration of deep mutational scanning and multi-faceted computational analyses.Journal of molecular biology · 2025Review
- Variant scoring tools for deep mutational scanning.Molecular systems biology · 2025Review
- Structural and functional analysis of theProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Deep mutational scanning of the multi-domain phosphatase SHP2 reveals mechanisms of regulation and pathogenicity.Nature communications · 2025Article
- Understanding, inhibiting, and engineering membrane transporters with high-throughput mutational screens.Cell chemical biology · 2025Review
- Conversion of Human Multidrug Transporter P-glycoprotein (ABCB1) from Drug Efflux to Uptake Pump: Evidence for a Switch Region Modulating the Direction of Substrate Transport.Journal of molecular biology · 2025Article
- Molecular basis of the functional conflict between chloroquine and peptide transport in the Malaria parasite chloroquine resistance transporter PfCRT.Nature communications · 2025Article
- Machine learning in molecular biophysics: Protein allostery, multi-level free energy simulations, and lipid phase transitions.Biophysics reviews · 2025Review
- The mycobacterial ABC transporter IrtAB employs a membrane-facing crevice for siderophore-mediated iron uptake.Nature communications · 2025Article
- A novel ABCC9 variant in a Greek family with Cantu syndrome affecting multiple generations highlights the functional role of the SUR2B NBD1.American journal of medical genetics. Part A · 2024Article
- Structural and functional diversity of Resistance-Nodulation-Division (RND) efflux pump transporters with implications for antimicrobial resistance.Microbiology and molecular biology reviews : MMBR · 2024Review
- Fitness landscape of substrate-adaptive mutations in evolved amino acid-polyamine-organocation transporters.eLife · 2024Article
- Peripheral positions encode transport specificity in the small multidrug resistance exporters.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Drug efflux is a common resistance mechanism found in bacteria and cancer cells, but studies providing comprehensive functional insights are scarce. In this study, we performed deep mutational scanning (DMS) on the bacterial ABC transporter EfrCD to determine the drug efflux activity profile of more than 1,430 single variants. These systematic measurements revealed that the introduction of negative charges at different locations within the large substrate binding pocket results in strongly increased efflux activity toward positively charged ethidium, whereas additional aromatic residues did not display the same effect. Data analysis in the context of an inward-facing cryogenic electron microscopy structure of EfrCD uncovered a high-affinity binding site, which releases bound drugs through a peristaltic transport mechanism as the transporter transits to its outward-facing conformation. Finally, we identified substitutions resulting in rapid Hoechst influx without affecting the efflux activity for ethidium and daunorubicin. Hence, single mutations can convert EfrCD into a drug-specific ABC importer.
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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.