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Manipulating Cation-π Interactions with Genetically Encoded Tryptophan Derivatives

  • Hongxia Zhao
    Hongxia Zhao
    Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
    More by Hongxia Zhao
  • Chao Liu
    Chao Liu
    Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
    More by Chao Liu
  • Wenlong Ding
    Wenlong Ding
    Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
    More by Wenlong Ding
  • Ling Tang
    Ling Tang
    Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
    More by Ling Tang
  • Yu Fang
    Yu Fang
    Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
    More by Yu Fang
  • Yulin Chen
    Yulin Chen
    Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
    More by Yulin Chen
  • Linzhen Hu
    Linzhen Hu
    Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
    More by Linzhen Hu
  • Ying Yuan
    Ying Yuan
    Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
    More by Ying Yuan
  • Dong Fang
    Dong Fang
    Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
    Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
    More by Dong Fang
  • , and 
  • Shixian Lin*
    Shixian Lin
    Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
    Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
    Cancer Center, Zhejiang University, Hangzhou 310058, China
    *Email: [email protected]
    More by Shixian Lin
Cite this: J. Am. Chem. Soc. 2022, 144, 15, 6742–6748
Publication Date (Web):April 5, 2022
https://doi.org/10.1021/jacs.1c12944
Copyright © 2022 American Chemical Society

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    Abstract

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    Cation-π interactions are the major noncovalent interactions for molecular recognition and play a central role in a broad area of chemistry and biology. Despite tremendous success in understanding the origin and biological importance of cation-π interactions, the design and synthesis of stronger cation-π interactions remain elusive. Here, we report an approach that greatly increases the binding energy of cation-π interactions by replacing Trp in the aromatic box with an electron-rich Trp derivative using the genetic code expansion strategy. The binding affinity between histone H3K4me3 and its reader is increased more than eightfold using genetically encoded 6-methoxy-Trp. Furthermore, through a systematic engineering process, we construct an H3K4me3 Super-Reader with single-digit nM affinity for H3K4me3 detection and imaging. More broadly, this approach paves the way for manipulating cation-π interactions for a variety of applications.

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    Cited By

    This article is cited by 6 publications.

    1. Laura Díaz-Casado, Alejandro Villacampa, Francisco Corzana, Jesús Jiménez-Barbero, Ana M. Gómez, Andrés G. Santana, Juan Luis Asensio. Illuminating a Solvent-Dependent Hierarchy for Aromatic CH/π Complexes with Dynamic Covalent Glyco-Balances. JACS Au 2024, 4 (2) , 476-490. https://doi.org/10.1021/jacsau.3c00592
    2. Wenlong Ding, Hongxia Zhao, Yulin Chen, Shixian Lin. New Strategies for Probing the Biological Functions of Protein Post-translational Modifications in Mammalian Cells with Genetic Code Expansion. Accounts of Chemical Research 2023, 56 (20) , 2827-2837. https://doi.org/10.1021/acs.accounts.3c00460
    3. Hongxia Zhao, Ling Tang, Yu Fang, Chao Liu, Wenlong Ding, Shunping Zang, Yulin Chen, Wenyuan Xu, Ying Yuan, Dong Fang, Shixian Lin. Manipulating Cation−π Interactions of Reader Proteins in Living Cells with Genetic Code Expansion. Journal of the American Chemical Society 2023, 145 (30) , 16406-16416. https://doi.org/10.1021/jacs.3c02293
    4. Jing-Fang Yang, Fan Wang, Meng-Yao Wang, Di Wang, Zhong-Shi Zhou, Ge-Fei Hao, Qing X. Li, Guang-Fu Yang. CIPDB: A biological structure databank for studying cation and π interactions. Drug Discovery Today 2023, 28 (5) , 103546. https://doi.org/10.1016/j.drudis.2023.103546
    5. Simon Bergsma, Efthymios Poulios, Nikolaos Charalampogiannis, Odetta Andraws, Spyridon Achinas. Cation-𝜋 Interaction as a Key Player in Healthcare: A Mini-Review. Digital Medicine and Healthcare Technology 2022, 2022 , 1-13. https://doi.org/10.5772/dmht.11
    6. Marijn N. Maas, Jordi C. J. Hintzen, Jasmin Mecinović. Probing lysine posttranslational modifications by unnatural amino acids. Chemical Communications 2022, 58 (52) , 7216-7231. https://doi.org/10.1039/D2CC00708H

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