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@ARTICLE{LaSala:1008583,
author = {La Sala, Giuseppina and Pfleger, Christopher and Käck,
Helena and Wissler, Lisa and Nevin, Philip and Böhm,
Kerstin and Janet, Jon Paul and Schimpl, Marianne and
Stubbs, Christopher J. and De Vivo, Marco and Tyrchan,
Christian and Hogner, Anders and Gohlke, Holger and Frolov,
Andrey I.},
title = {{C}ombining structural and coevolution information to
unveil allosteric sites},
journal = {Chemical science},
volume = {14},
number = {25},
issn = {2041-6520},
address = {Cambridge},
publisher = {RSC},
reportid = {FZJ-2023-02416},
pages = {7057-7067},
year = {2023},
note = {This is an open access publication.},
abstract = {Understanding allosteric regulation in biomolecules is of
great interest to pharmaceutical research and computational
methods emerged during the last decades to characterize
allosteric coupling. However, the prediction of allosteric
sites in a protein structure remains a challenging task.
Here, we integrate local binding site information,
coevolutionary information, and information on dynamic
allostery into a structure-based three-parameter model to
identify potentially hidden allosteric sites in ensembles of
protein structures with orthosteric ligands. When tested on
five allosteric proteins (LFA-1, p38-α, GR, MAT2A, and
BCKDK), the model successfully ranked all known allosteric
pockets in the top three positions. Finally, we identified a
novel druggable site in MAT2A confirmed by X-ray
crystallography and SPR and a hitherto unknown druggable
allosteric site in BCKDK validated by biochemical and X-ray
crystallography analyses. Our model can be applied in drug
discovery to identify allosteric pockets.},
cin = {NIC / JSC / IBI-7 / IBG-4},
ddc = {540},
cid = {I:(DE-Juel1)NIC-20090406 / I:(DE-Juel1)JSC-20090406 /
I:(DE-Juel1)IBI-7-20200312 / I:(DE-Juel1)IBG-4-20200403},
pnm = {5111 - Domain-Specific Simulation $\&$ Data Life Cycle Labs
(SDLs) and Research Groups (POF4-511) / 2171 - Biological
and environmental resources for sustainable use (POF4-217) /
Forschergruppe Gohlke $(hkf7_20200501)$},
pid = {G:(DE-HGF)POF4-5111 / G:(DE-HGF)POF4-2171 /
$G:(DE-Juel1)hkf7_20200501$},
typ = {PUB:(DE-HGF)16},
pubmed = {37389247},
UT = {WOS:001004486700001},
doi = {10.1039/D2SC06272K},
url = {https://juser.fz-juelich.de/record/1008583},
}