Issue 19, 2020

Nucleic acid constructs for the interrogation of multivalent protein interactions


Multivalency is nature's way to establish firm and specific interactions when the binding sites of a protein receptor have only low affinity for monovalent ligands. Recently, researchers are increasingly using nucleic acid architectures for multivalent ligand presentation to unravel the mechanisms of multivalency-enhanced interactions and create high affinity binding agents. In contrast to other polymers, nucleic acid materials are capable of accessing a wide variety of rigid three-dimensional structures through the sequence-programed self-assembly of component strands. By controlling the number of ligands and their distances, researchers can construct tailor-made probes for interrogating multivalent interactions with Ångstrom precision. Nucleic acid assemblies have been used to address fundamental questions of multivalency in order to unravel how monovalent interaction strength, scaffold flexibility, distances between interacting sites and spatial arrangement influence the achievable affinity gains. In a slightly different approach, nucleic acid constructs have been applied as chemical dimerizers of protein receptors, to investigate the importance of receptor proximity or construct tools that provide control over biological signal transduction processes. In this review, we discuss multivalent nucleic acid–ligand conjugates in the context of the biological protein receptors they interrogate. We recount pioneering work and seminal studies performed within the last 10 years describing the in vitro interrogation of proteins recognizing carbohydrate ligands, small molecules, peptides and nucleic acid aptamers and we portray work performed with viruses, cell models, and whole organisms.

Graphical abstract: Nucleic acid constructs for the interrogation of multivalent protein interactions

Article information

Article type
Tutorial Review
08 May 2020
First published
01 Sep 2020
This article is Open Access
Creative Commons BY license

Chem. Soc. Rev., 2020,49, 6848-6865

Nucleic acid constructs for the interrogation of multivalent protein interactions

S. B. Yeldell and O. Seitz, Chem. Soc. Rev., 2020, 49, 6848 DOI: 10.1039/D0CS00518E

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