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@ARTICLE{Mehlman:612788,
author = {Mehlman, Tamar and Ginn, Helen M. and Keedy, Daniel A.},
title = {{A}n expanded trove of fragment-bound structures for the
allosteric enzyme {PTP}1{B} from computational reanalysis of
large-scale crystallographic data},
journal = {Structure},
volume = {32},
number = {8},
issn = {0969-2126},
address = {Cambridge, Mass.},
publisher = {Cell Press},
reportid = {PUBDB-2024-05462},
pages = {1231 - 1238.e4},
year = {2024},
note = {Waiting for fulltext},
abstract = {Due to their low binding affinities, detecting
small-molecule fragments bound to protein structures from
crystallographic datasets has been a challenge. Here, we
report a trove of 65 new fragment hits for PTP1B, an
“undruggable” therapeutic target enzyme for diabetes and
cancer. These structures were obtained from computational
analysis of data from a large crystallographic screen,
demonstrating the power of this approach to elucidate many
$(∼50\%$ more) “hidden” ligand-bound states of
proteins. Our new structures include a fragment hit found in
a novel binding site in PTP1B with a unique location
relative to the active site, one that links adjacent
allosteric sites, and, perhaps most strikingly, a fragment
that induces long-range allosteric protein conformational
responses. Altogether, our research highlights the utility
of computational analysis of crystallographic data, makes
publicly available dozens of new ligand-bound structures of
a high-value drug target, and identifies novel aspects of
ligandability and allostery in PTP1B.},
cin = {FS-CFEL-1-DNMX},
ddc = {540},
cid = {I:(DE-H253)FS-CFEL-1-DNMX-20231108},
pnm = {633 - Life Sciences – Building Blocks of Life: Structure
and Function (POF4-633) / VH-NG-19-02 - Working with RoPE:
Representation of Protein Entities $(2023_IVF-VH-NG-19-02)$
/ DFG project G:(GEPRIS)390715994 - EXC 2056: CUI: Tiefe
Einblicke in Materie (390715994)},
pid = {G:(DE-HGF)POF4-633 / $G:(DE-HGF)2023_IVF-VH-NG-19-02$ /
G:(GEPRIS)390715994},
experiment = {EXP:(DE-MLZ)NOSPEC-20140101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38861991},
UT = {WOS:001292191500001},
doi = {10.1016/j.str.2024.05.010},
url = {https://bib-pubdb1.desy.de/record/612788},
}