Journal article
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 former manifesting lower Mg2+/Mn2+ KMs. The isocitrate-Mg2+ complex is the preferred wt IDH1 substrate; with R132H IDH1, separate and weaker binding of 2-oxoglutarate and Mg2+ is preferred. Binding of R132H IDH1 inhibitors at the dimer interface weakens binding of active site Mg2+ complexes; their potency is affected by the Mg2+ concentration. Inhibitor selectivity for R132H IDH1 over wt IDH1 substantially arises from different stabilities of wt and R132H IDH1 substrate-Mg2+ complexes. The results reveal the importance of substrate-metal ion complexes in wt and R132H IDH1 catalysis and the basis for selective R132H IDH1 inhibition. Further studies on roles of metal ion complexes in TCA cycle and related metabolism, including from an evolutionary perspective, are of interest.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 3.8MB, Terms of use)
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- Publisher copy:
- 10.1038/s42003-021-02743-5
Authors
- Publisher:
- Springer Nature
- Journal:
- Communications Biology More from this journal
- 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:
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pubs:1207517
- Deposit date:
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2021-11-18
Terms of use
- Copyright holder:
- Liu et al.
- Copyright date:
- 2021
- Rights statement:
- © The Author(s) 2021. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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