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Roles of metal ions in the selective inhibition of oncogenic variants of isocitrate dehydrogenase 1

Abstract:

Cancer linked isocitrate dehydrogenase (IDH) 1 variants, notably R132H IDH1, manifest a ‘gain-of-function’ to reduce 2-oxoglutarate to 2-hydroxyglutarate. High-throughput screens have enabled clinically useful R132H IDH1 inhibitors, mostly allosteric binders at the dimer interface. We report investigations on roles of divalent metal ions in IDH substrate and inhibitor binding that rationalise this observation. Mg2+/Mn2+ ions enhance substrate binding to wt IDH1 and R132H IDH1, but with the fo...

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Publication status:
Published
Peer review status:
Peer reviewed

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Publisher copy:
10.1038/s42003-021-02743-5

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Role:
Author
ORCID:
0000-0003-3287-2404
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Role:
Author
ORCID:
0000-0002-6123-595X
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Role:
Author
ORCID:
0000-0002-3205-9969
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RCUK | Engineering and Physical Sciences Research Council (EPSRC) More from this funder
Publisher:
Springer Nature Publisher's website
Journal:
Communications Biology Journal website
Volume:
4
Issue:
1
Article number:
1243
Place of publication:
England
Publication date:
2021-11-01
Acceptance date:
2021-10-04
DOI:
EISSN:
2399-3642
Language:
English
Keywords:
Pubs id:
1207517
Local pid:
pubs:1207517
Deposit date:
2021-11-18

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