7s95 | pdb_00007s95
Room-temperature Human Hsp90a-NTD bound to adenine
Structural highlights
Function[HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.[1] [2] Publication Abstract from PubMedHigh-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 Hsp90alpha, 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. Water Networks Repopulate Protein-Ligand Interfaces with Temperature.,Stachowski TR, Vanarotti M, Seetharaman J, Lopez K, Fischer M Angew Chem Int Ed Engl. 2022 Aug 1;61(31):e202112919. doi:, 10.1002/anie.202112919. Epub 2022 Jun 21. PMID:35648650[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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