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Traceless cysteine-linchpin enables precision engineering of lysine in native proteins

Author

Listed:
  • Neelesh C. Reddy

    (Indian Institute of Science Education and Research Bhopal)

  • Rajib Molla

    (Indian Institute of Science Education and Research Bhopal)

  • Pralhad Namdev Joshi

    (Indian Institute of Science Education and Research Bhopal)

  • Sajeev T. K.

    (Indian Institute of Science Education and Research Bhopal)

  • Ipsita Basu

    (S. N. Bose National Centre for Basic Sciences, Block-JD, Sector-III, Salt Lake)

  • Jyotsna Kawadkar

    (Indian Institute of Science Education and Research Bhopal)

  • Neetu Kalra

    (School of Bioengineering)

  • Ram Kumar Mishra

    (Indian Institute of Science Education and Research Bhopal)

  • Suman Chakrabarty

    (S. N. Bose National Centre for Basic Sciences, Block-JD, Sector-III, Salt Lake)

  • Sanjeev Shukla

    (Indian Institute of Science Education and Research Bhopal)

  • Vishal Rai

    (Indian Institute of Science Education and Research Bhopal)

Abstract

The maintenance of machinery requires its operational understanding and a toolbox for repair. The methods for the precision engineering of native proteins meet a similar requirement in biosystems. Its success hinges on the principles regulating chemical reactions with a protein. Here, we report a technology that delivers high-level control over reactivity, chemoselectivity, site-selectivity, modularity, dual-probe installation, and protein-selectivity. It utilizes cysteine-based chemoselective Linchpin-Directed site-selective Modification of lysine residue in a protein (LDMC-K). The efficiency of the end-user-friendly protocol is evident in quantitative conversions within an hour. A chemically orthogonal C-S bond-formation and bond-dissociation are essential among multiple regulatory attributes. The method offers protein selectivity by targeting a single lysine residue of a single protein in a complex biomolecular mixture. The protocol renders analytically pure single-site probe-engineered protein bioconjugate. Also, it provides access to homogeneous antibody conjugates (AFC and ADC). The LDMC-K-ADC exhibits highly selective anti-proliferative activity towards breast cancer cells.

Suggested Citation

  • Neelesh C. Reddy & Rajib Molla & Pralhad Namdev Joshi & Sajeev T. K. & Ipsita Basu & Jyotsna Kawadkar & Neetu Kalra & Ram Kumar Mishra & Suman Chakrabarty & Sanjeev Shukla & Vishal Rai, 2022. "Traceless cysteine-linchpin enables precision engineering of lysine in native proteins," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33772-1
    DOI: 10.1038/s41467-022-33772-1
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    References listed on IDEAS

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    1. Landa Purushottam & Srinivasa Rao Adusumalli & Usha Singh & V. B. Unnikrishnan & Dattatraya Gautam Rawale & Mansi Gujrati & Ram Kumar Mishra & Vishal Rai, 2019. "Single-site glycine-specific labeling of proteins," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
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    Cited by:

    1. Yuwen Wang & Patrick Czabala & Monika Raj, 2023. "Bioinspired one-pot furan-thiol-amine multicomponent reaction for making heterocycles and its applications," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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