7S9I

Room-temperature Human Hsp90a-NTD bound to EC144

Summary for 7S9I

• Entry DOI: 10.2210/pdb7s9i/pdb
• Descriptor: Heat shock protein HSP 90-alpha, 5-{2-amino-4-chloro-7-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methylpent-4-yn-2 -ol (3 entities in total)
• Functional Keywords: heat shock, chaperone, signaling, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 27153.82

Authors

Stachowski, T.R.,Vanarotti, M.,Fischer, M. (deposition date: 2021-09-21, release date: 2022-08-03, Last modification date: 2023-10-18)

Primary citation

Stachowski, T.R.,Vanarotti, M.,Seetharaman, J.,Lopez, K.,Fischer, M.
Water Networks Repopulate Protein-Ligand Interfaces with Temperature.
Angew.Chem.Int.Ed.Engl., 61:e202112919-e202112919, 2022

PubMed 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.

PubMed: 35648650
DOI: 10.1002/anie.202112919

Experimental method

X-RAY DIFFRACTION (1.75 Å)