Metal coordination and enzymatic reaction of the glioma-target R132H isocitrate dehydrogenase 1: Insights by molecular simulations.
R132H IDH1 is an important therapeutic target for a variety of brain cancers, yet drug leads and radiotracers which selectively bind only to the mutant over the wild type are so far lacking. Here we have predicted the structural determinants of the Michaelis complex of this mutant using a QM/MM MD-b...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0326425 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850108411078770688 |
|---|---|
| author | Bharath Raghavan Marco De Vivo Paolo Carloni |
| author_facet | Bharath Raghavan Marco De Vivo Paolo Carloni |
| author_sort | Bharath Raghavan |
| collection | DOAJ |
| description | R132H IDH1 is an important therapeutic target for a variety of brain cancers, yet drug leads and radiotracers which selectively bind only to the mutant over the wild type are so far lacking. Here we have predicted the structural determinants of the Michaelis complex of this mutant using a QM/MM MD-based protocol. It shows some important differences with the X-ray structure, from the metal coordination to the positioning of key residues at the active site. In particular, one lysine residue (K212) emerges as a mostly likely proton donor in the key proton-transfer step of the R132H IDH1 catalytic reaction. Intriguingly, the same residue in its deprotonated state is likely to be involved in the reaction catalyzed by the wild-type enzyme (though the mechanisms are different). Our QM/MM protocol could also be used for other metal-based enzymes, which cannot be modelled easily by force field-based MD, like in this case. |
| format | Article |
| id | doaj-art-a2632519dc5442c3b03e2a5e4012cab9 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-a2632519dc5442c3b03e2a5e4012cab92025-08-20T02:38:22ZengPublic Library of Science (PLoS)PLoS ONE1932-62032025-01-01206e032642510.1371/journal.pone.0326425Metal coordination and enzymatic reaction of the glioma-target R132H isocitrate dehydrogenase 1: Insights by molecular simulations.Bharath RaghavanMarco De VivoPaolo CarloniR132H IDH1 is an important therapeutic target for a variety of brain cancers, yet drug leads and radiotracers which selectively bind only to the mutant over the wild type are so far lacking. Here we have predicted the structural determinants of the Michaelis complex of this mutant using a QM/MM MD-based protocol. It shows some important differences with the X-ray structure, from the metal coordination to the positioning of key residues at the active site. In particular, one lysine residue (K212) emerges as a mostly likely proton donor in the key proton-transfer step of the R132H IDH1 catalytic reaction. Intriguingly, the same residue in its deprotonated state is likely to be involved in the reaction catalyzed by the wild-type enzyme (though the mechanisms are different). Our QM/MM protocol could also be used for other metal-based enzymes, which cannot be modelled easily by force field-based MD, like in this case.https://doi.org/10.1371/journal.pone.0326425 |
| spellingShingle | Bharath Raghavan Marco De Vivo Paolo Carloni Metal coordination and enzymatic reaction of the glioma-target R132H isocitrate dehydrogenase 1: Insights by molecular simulations. PLoS ONE |
| title | Metal coordination and enzymatic reaction of the glioma-target R132H isocitrate dehydrogenase 1: Insights by molecular simulations. |
| title_full | Metal coordination and enzymatic reaction of the glioma-target R132H isocitrate dehydrogenase 1: Insights by molecular simulations. |
| title_fullStr | Metal coordination and enzymatic reaction of the glioma-target R132H isocitrate dehydrogenase 1: Insights by molecular simulations. |
| title_full_unstemmed | Metal coordination and enzymatic reaction of the glioma-target R132H isocitrate dehydrogenase 1: Insights by molecular simulations. |
| title_short | Metal coordination and enzymatic reaction of the glioma-target R132H isocitrate dehydrogenase 1: Insights by molecular simulations. |
| title_sort | metal coordination and enzymatic reaction of the glioma target r132h isocitrate dehydrogenase 1 insights by molecular simulations |
| url | https://doi.org/10.1371/journal.pone.0326425 |
| work_keys_str_mv | AT bharathraghavan metalcoordinationandenzymaticreactionofthegliomatargetr132hisocitratedehydrogenase1insightsbymolecularsimulations AT marcodevivo metalcoordinationandenzymaticreactionofthegliomatargetr132hisocitratedehydrogenase1insightsbymolecularsimulations AT paolocarloni metalcoordinationandenzymaticreactionofthegliomatargetr132hisocitratedehydrogenase1insightsbymolecularsimulations |