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Ligand-specific changes in conformational flexibility mediate long-range allostery in the lac repressor

Author

Listed:
  • Anum Glasgow

    (University of California
    Columbia University)

  • Helen T. Hobbs

    (University of California, Berkeley)

  • Zion R. Perry

    (Yale University)

  • Malcolm L. Wells

    (Columbia University)

  • Susan Marqusee

    (University of California, Berkeley
    University of California, Berkeley)

  • Tanja Kortemme

    (University of California)

Abstract

Biological regulation ubiquitously depends on protein allostery, but the regulatory mechanisms are incompletely understood, especially in proteins that undergo ligand-induced allostery with few structural changes. Here we used hydrogen-deuterium exchange with mass spectrometry (HDX/MS) to map allosteric effects in a paradigm ligand-responsive transcription factor, the lac repressor (LacI), in different functional states (apo, or bound to inducer, anti-inducer, and/or DNA). Although X-ray crystal structures of the LacI core domain in these states are nearly indistinguishable, HDX/MS experiments reveal widespread differences in flexibility. We integrate these results with modeling of protein-ligand-solvent interactions to propose a revised model for allostery in LacI, where ligand binding allosterically shifts the conformational ensemble as a result of distinct changes in the rigidity of secondary structures in the different states. Our model provides a mechanistic basis for the altered function of distal mutations. More generally, our approach provides a platform for characterizing and engineering protein allostery.

Suggested Citation

  • Anum Glasgow & Helen T. Hobbs & Zion R. Perry & Malcolm L. Wells & Susan Marqusee & Tanja Kortemme, 2023. "Ligand-specific changes in conformational flexibility mediate long-range allostery in the lac repressor," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36798-1
    DOI: 10.1038/s41467-023-36798-1
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    References listed on IDEAS

    as
    1. Daniel J Parente & Liskin Swint-Kruse, 2013. "Multiple Co-Evolutionary Networks Are Supported by the Common Tertiary Scaffold of the LacI/GalR Proteins," PLOS ONE, Public Library of Science, vol. 8(12), pages 1-17, December.
    2. Xian-Li Jiang & Rey P. Dimas & Clement T. Y. Chan & Faruck Morcos, 2021. "Coevolutionary methods enable robust design of modular repressors by reestablishing intra-protein interactions," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    3. Ryan E Pavlovicz & Hahnbeom Park & Frank DiMaio, 2020. "Efficient consideration of coordinated water molecules improves computational protein-protein and protein-ligand docking discrimination," PLOS Computational Biology, Public Library of Science, vol. 16(9), pages 1-20, September.
    4. Javier F. Juárez & Begoña Lecube-Azpeitia & Stuart L. Brown & Christopher D. Johnston & George M. Church, 2018. "Biosensor libraries harness large classes of binding domains for construction of allosteric transcriptional regulators," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
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