7ur3

Hsp90 alpha inhibitorHsp90 alpha inhibitor

Structural highlights 7ur3 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. Publication Abstract from PubMed The heat shock protein 90 (Hsp90) family of molecular chaperones mediates the folding and activation of client proteins associated with all 10 hallmarks of cancer. Herein, the design, synthesis, and biological validation of Hsp90alpha-selective inhibitors that contain a tertiary alcohol are reported. Forty-one analogues were synthesized to modulate hydrogen-bonding interactions and to probe for steric and hydrophobic interactions within the Hsp90alpha binding site. Cocrystal structures of lead compound 23d (IC(50) = 0.25 muM, 15-fold selective vs Hsp90beta) and a 5-fluoroisoindoline derivative (KUNA-111) revealed a novel binding mode that induced conformational changes within Hsp90alpha's N-terminal domain. The lead Hsp90alpha-selective inhibitors did not manifest significant antiproliferative activity, but they did result in selective and dose-dependent degradation of Hsp90alpha clients in the cellular environment. Additional studies will be sought to determine the effects of the novel conformational change induced by 23d. Structure-Activity Relationship Study of Tertiary Alcohol Hsp90alpha-Selective Inhibitors with Novel Binding Mode.,Mishra SJ, Reynolds TS, Merfeld T, Balch M, Peng S, Deng J, Matts R, Blagg BSJ ACS Med Chem Lett. 2022 Nov 4;13(12):1870-1878. doi: , 10.1021/acsmedchemlett.2c00327. eCollection 2022 Dec 8. PMID:36518703 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Heat Shock Protein structures

spinqualitylabelsall models 7ur3, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image