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


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.

SUBMITTER: Reddy NC 

PROVIDER: S-EPMC9561114 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Reddy Neelesh C NC   Molla Rajib R   Joshi Pralhad Namdev PN   T K Sajeev S   Basu Ipsita I   Kawadkar Jyotsna J   Kalra Neetu N   Mishra Ram Kumar RK   Chakrabarty Suman S   Shukla Sanjeev S   Rai Vishal V  

Nature communications 20221013 1


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 L  ...[more]

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