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@ARTICLE{Koruza:872857,
author = {Koruza, Katarina and Mahon, Brian P. and Blakeley, Matthew
P. and Ostermann, Andreas and Schrader, Tobias E. and
McKenna, Robert and Knecht, Wolfgang and Fisher, S. Zoë},
title = {{U}sing neutron crystallography to elucidate the basis of
selective inhibition of carbonic anhydrase by saccharin and
a derivative},
journal = {Journal of structural biology},
volume = {205},
number = {2},
issn = {1047-8477},
address = {San Diego, Calif.},
publisher = {Elsevier},
reportid = {FZJ-2020-00325},
pages = {147 - 154},
year = {2019},
abstract = {Up-regulation of carbonic anhydrase IX (CA IX) expression
is an indicator of metastasis and associated with poorcancer
patient prognosis. CA IX has emerged as a cancer drug target
but development of isoform-specific inhibitorsis challenging
due to other highly conserved CA isoforms. In this study, a
CA IXmimic construct was used(CA II with seven point
mutations introduced, to mimic CA IX active site) while
maintaining CA II solubility thatmake it amenable to
crystallography. The structures of CA IXmimic unbound and in
complex with saccharin (SAC)and a saccharin-glucose
conjugate (SGC) were determined using joint X-ray and
neutron protein crystallography.Previously, SAC and SGC have
been shown to display CA isoform inhibitor selectivity in
assays and X-ray crystalstructures failed to reveal the
basis of this selectivity. Joint X-ray and neutron
crystallographic studies haveshown active site residues,
solvent, and H-bonding re-organization upon SAC and SGC
binding. These observationshighlighted the importance of
residues 67 (Asn in CA II, Gln in CA IX) and 130 (Asp in CA
II, Arg in CAIX) in selective CA inhibitor targeting.},
cin = {JCNS-FRM-II / JCNS-1 / MLZ},
ddc = {540},
cid = {I:(DE-Juel1)JCNS-FRM-II-20110218 /
I:(DE-Juel1)JCNS-1-20110106 / I:(DE-588b)4597118-3},
pnm = {6G4 - Jülich Centre for Neutron Research (JCNS) (POF3-623)
/ 6G15 - FRM II / MLZ (POF3-6G15) / 6215 - Soft Matter,
Health and Life Sciences (POF3-621)},
pid = {G:(DE-HGF)POF3-6G4 / G:(DE-HGF)POF3-6G15 /
G:(DE-HGF)POF3-6215},
experiment = {EXP:(DE-MLZ)BIODIFF-20140101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30639924},
UT = {WOS:000460494000004},
doi = {10.1016/j.jsb.2018.12.009},
url = {https://juser.fz-juelich.de/record/872857},
}