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Ligand promiscuity in the tryptophan repressor – from structural understanding towards rational design

Andre C. Stiel, Sooruban Shanmugaratnam, Ole Herud-Sikimic, Gerd Jürgens, Birte Höcker
doi: https://doi.org/10.1101/2020.01.20.912972
Andre C. Stiel
1Max Planck Institute for Developmental Biology, Tübingen, Germany
2Institute for Biological and Medical Imaging, Helmholtz Zentrum Munich, German Research Center for Environmental Health, München, Germany
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Sooruban Shanmugaratnam
1Max Planck Institute for Developmental Biology, Tübingen, Germany
3Lehrstuhl für Biochemie, Universität Bayreuth, Bayreuth, Germany
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Ole Herud-Sikimic
1Max Planck Institute for Developmental Biology, Tübingen, Germany
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Gerd Jürgens
1Max Planck Institute for Developmental Biology, Tübingen, Germany
4Center for Plant Molecular Biology, University of Tübingen, Tübingen, Germany
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Birte Höcker
1Max Planck Institute for Developmental Biology, Tübingen, Germany
3Lehrstuhl für Biochemie, Universität Bayreuth, Bayreuth, Germany
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  • For correspondence: Birte.Hoecker@uni-bayreuth.de
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Abstract

Receptors that promiscuously bind a range of ligands provide insights into how nature mediates affinity and biological functioning. Moreover, such receptors provide vantage points for the rational design of specific binding for biotechnological applications. Here we describe the molecular details of the ligand binding promiscuity of the well-known tryptophan repressor TrpR. We elucidated high-resolution structures of TrpR bound to the co-repressors 5-methyl-tryptophan and 5-methyl-tryptamine as well as the pseudo-repressors indole-3-propionic and indole-3-acetic acid. Furthermore, using isothermal titration calorimetry we procure the corresponding thermodynamic parameters. Together this data provides molecular explanations for the strongly varied affinities and biological effects of the ligands providing insights into how nature shapes specificity and affinity. Beyond this we use these insights to exemplarily showcase knowledge-based design of TrpR by swapping its specificity from its native ligand tryptophan to indole-3-acetic acid. Finally, we elucidate the structures of the variant bound to indole-3-acetic and indole-3-propionic acid to retrace our design rationale.

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Posted January 21, 2020.
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Ligand promiscuity in the tryptophan repressor – from structural understanding towards rational design
Andre C. Stiel, Sooruban Shanmugaratnam, Ole Herud-Sikimic, Gerd Jürgens, Birte Höcker
bioRxiv 2020.01.20.912972; doi: https://doi.org/10.1101/2020.01.20.912972
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Ligand promiscuity in the tryptophan repressor – from structural understanding towards rational design
Andre C. Stiel, Sooruban Shanmugaratnam, Ole Herud-Sikimic, Gerd Jürgens, Birte Höcker
bioRxiv 2020.01.20.912972; doi: https://doi.org/10.1101/2020.01.20.912972

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