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

Neelesh C. Reddy, Rajib Molla, Pralhad Namdev Joshi, Sajeev T. K., Ipsita Basu, Jyotsna Kawadkar, Neetu Kalra, Ram Kumar Mishra, Suman Chakrabarty, Sanjeev Shukla and Vishal Rai ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33772-1

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