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Highly multiplexed design of an allosteric transcription factor to sense new ligands

Nature Communications, ISSN: 2041-1723, Vol: 15, Issue: 1, Page: 10001
2024
  • 0
    Citations
  • 0
    Usage
  • 0
    Captures
  • 4
    Mentions
  • 10
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Mentions
    4
    • News Mentions
      4
      • News
        4
  • Social Media
    10
    • Shares, Likes & Comments
      10
      • Facebook
        10

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Article Description

Allosteric transcription factors (aTF) regulate gene expression through conformational changes induced by small molecule binding. Although widely used as biosensors, aTFs have proven challenging to design for detecting new molecules because mutation of ligand-binding residues often disrupts allostery. Here, we develop Sensor-seq, a high-throughput platform to design and identify aTF biosensors that bind to non-native ligands. We screen a library of 17,737 variants of the aTF TtgR, a regulator of a multidrug exporter, against six non-native ligands of diverse chemical structures – four derivatives of the cancer therapeutic tamoxifen, the antimalarial drug quinine, and the opiate analog naltrexone – as well as two native flavonoid ligands, naringenin and phloretin. Sensor-seq identifies biosensors for each of these ligands with high dynamic range and diverse specificity profiles. The structure of a naltrexone-bound design shows shape-complementary methionine-aromatic interactions driving ligand specificity. To demonstrate practical utility, we develop cell-free detection systems for naltrexone and quinine. Sensor-seq enables rapid and scalable design of new biosensors, overcoming constraints of natural biosensors.

Bibliographic Details

Nishikawa, Kyle K; Chen, Jackie; Acheson, Justin F; Harbaugh, Svetlana V; Huss, Phil; Frenkel, Max; Novy, Nathan; Sieren, Hailey R; Lodewyk, Ella C; Lee, Daniel H; Chávez, Jorge L; Fox, Brian G; Raman, Srivatsan

Springer Science and Business Media LLC

Chemistry; Biochemistry, Genetics and Molecular Biology; Physics and Astronomy

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