Water Networks Repopulate Protein–Ligand Interfaces with Temperature
Abstract: High‐resolution crystal structures highlight the importance of water networks in protein–ligand interactions. However, as these are typically determined at cryogenic temperature, resulting insights may be structurally precise but not biologically accurate. By collecting 10 matched room‐temperature and cryogenic datasets of the biomedical target Hsp90α, we identified changes in water networks that impact protein conformations at the ligand binding interface. Water repositioning with temperature repopulates protein ensembles and ligand interactions. We introduce Flipper conformational barcodes to identify temperature‐sensitive regions in electron density maps. This revealed that temperature‐responsive states coincide with ligand‐responsive regions and capture unique binding signatures that disappear upon cryo‐cooling. Our results have implications for discovering Hsp90 selective ligands, and, more generally, for the utility of hidden protein and water conformations in drug discovery.
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Erschienen in
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Water Networks Repopulate Protein–Ligand Interfaces with Temperature ; day:20 ; month:06 ; year:2022 ; extent:1
Angewandte Chemie ; (20.06.2022) (gesamt 1)
- Urheber
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Stachowski, Timothy R.
Vanarotti, Murugendra
Seetharaman, Jayaraman
Lopez, Karlo
Fischer, Marcus
- DOI
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10.1002/ange.202112919
- URN
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urn:nbn:de:101:1-2022062115063002237030
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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15.08.2025, 07:35 MESZ
Datenpartner
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.
Beteiligte
- Stachowski, Timothy R.
- Vanarotti, Murugendra
- Seetharaman, Jayaraman
- Lopez, Karlo
- Fischer, Marcus
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