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@ARTICLE{Raghavan:1044405,
author = {Raghavan, Bharath and De Vivo, Marco and Carloni, Paolo},
title = {{M}etal coordination and enzymatic reaction of the
glioma-target {R}132{H} isocitrate dehydrogenase 1:
{I}nsights by molecular simulations},
journal = {PLOS ONE},
volume = {20},
number = {6},
issn = {1932-6203},
address = {San Francisco, California, US},
publisher = {PLOS},
reportid = {FZJ-2025-03169},
pages = {e0326425},
year = {2025},
note = {Open access},
abstract = {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.},
cin = {INM-9},
ddc = {610},
cid = {I:(DE-Juel1)INM-9-20140121},
pnm = {5241 - Molecular Information Processing in Cellular Systems
(POF4-524)},
pid = {G:(DE-HGF)POF4-5241},
typ = {PUB:(DE-HGF)16},
doi = {10.1371/journal.pone.0326425},
url = {https://juser.fz-juelich.de/record/1044405},
}