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Disulfide bridge cross-linking between protein and the RNA backbone as a tool to study RNase H1.

Abstract：

:The chemical cross-linking of complexes of proteins with nucleic acids is often used in structural and mechanistic studies of these oftentimes unstable and transient complexes. To date, no method has been reported for the thiol-based conjugation of proteins with an RNA backbone, mainly because of instability of the modified ribonucleic acid that is functionalized at the phosphodiester and its rapid hydrolysis. Here, we report the site-specific synthesis of stable RNA oligonucleotides with a thiol-bearing linker that was attached to the phosphodiester backbone, where the ribonucleotide at the cross-linking site was either replaced with 2'-deoxy- or 2'-fluororibonucleotide. The utility of this approach was validated in cross-linking tests with RNase H1, a model protein for RNA/DNA binding and key effector in DNA-like antisense drug therapy. Furthermore, scale-up cross-linking and purification of the complexes confirmed that the method is useful for obtaining preparations of protein-RNA/DNA complexes with purity and stability that are suitable for further biochemical and structural studies. The present approach broadens the repertoire of disulfide-based cross-linking strategies and is a novel tool for the stabilization of protein-RNA complexes in which the interaction occurs via the RNA backbone. This methodology may be broadly applicable to studies of otherwise unstable or transient complexes of proteins with RNA and RNA/DNA.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Hyjek-Składanowska M,Stasińska AR,Napiórkowska-Gromadzka A,Bartłomiejczak A,Seth PP,Chmielewski MK,Nowotny M

doi

10.1016/j.bmc.2020.115741

subject

Has Abstract

pub_date

2020-12-01 00:00:00

pages

115741

issue

23

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(20)30571-X

journal_volume

28

pub_type

杂志文章

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