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research article

Crosslinking Allosteric Sites on the Nucleosome

Batchelor, Lucinda K.  
•
De Falco, Louis
•
von Erlach, Thibaud  
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September 18, 2019
Angewandte Chemie International Edition

Targeting defined histone protein sites in chromatin is an emerging therapeutic approach that can potentially be enhanced by allosteric effects within the nucleosome. Here we characterized a novel hetero-bimetallic compound with a design based on a nucleosomal allostery effect observed earlier for two unrelated drugs-the Ru-II antimetastasis/antitumor RAPTA-T and the Au-I anti-arthritic auranofin. The Ru-II moiety binds specifically to two H2A glutamate residues on the nucleosome acidic patch, allosterically triggering a cascade of structural changes that promote binding of the Au-I moiety to selective histidine residues on H3, resulting in cross-linking sites that are over 35 angstrom distant. By tethering the H2A-H2B dimers to the H3-H4 tetramer, the hetero-bimetallic compound significantly increases stability of the nucleosome, illustrating its utility as a site-selective cross-linking agent.

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Type
research article
DOI
10.1002/anie.201906423
Web of Science ID

WOS:000486819000001

Author(s)
Batchelor, Lucinda K.  
De Falco, Louis
von Erlach, Thibaud  
Sharma, Deepti
Adhireksan, Zenita
Roethlisberger, Ursula  
Davey, Curt A.
Dyson, Paul J.  
Date Issued

2019-09-18

Publisher

Wiley-VCH Verlag GmbH

Published in
Angewandte Chemie International Edition
Volume

58

Issue

44

Start page

15660

End page

15664

Subjects

Chemistry, Multidisciplinary

•

Chemistry

•

allostery

•

bioinorganic chemistry

•

macromolecular crystallography

•

molecular dynamics simulations

•

nucleosome structure

•

crystal-structure

•

chromatin

•

protein

•

drug

•

mechanisms

•

modulation

•

surface

•

cancer

•

dna

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
LCBC  
LCOM  
Available on Infoscience
October 3, 2019
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/161780
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