6ksq | pdb_00006ksq
Middle Domain of Human HSP90 Alpha
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 PubMedHsp90 is a target for anti-cancer drug development. Both the conformational events tuned by ATP/ADP and co-chaperones and the chaperoning cycle timing are required for Hsp90's fully functional display. Interfering with either one of the conformational events or the cycle timing will down-regulate Hsp90's function. In this manuscript, non-covalent allosteric modulators (SOMCL-16-171 and SOMCL-16-175) targeting Hsp90alpha's middle domain (Hsp90M) were developed for the first time. Multiple techniques were then applied to characterize the interactions between two active compounds and Hsp90alpha. Two loops and one alpha-helix (F349-N360, K443-E451, and D372-G387) in Hsp90M were identified responsible for the recognition of SOMCL-16-171 and SOMCL-16-175. Meanwhile, the binding of SOMCL-16-171 and SOMCL-16-175 to Hsp90M was demonstrated to allosterically modulate the structure and function of Hsp90alpha's N-terminal domain. Finally, cellular assays were conducted to evaluate the cellular activity of SOMCL-16-175, and the results indicate that SOMCL-16-175 destabilizes Hsp90's client proteins and reduces cell viability. Allosteric Regulation of Hsp90alpha's Activity by Small Molecules Targeting the Middle Domain of the Chaperone.,Zhou C, Zhang C, Zhu H, Liu Z, Su H, Zhang X, Chen T, Zhong Y, Hu H, Xiong M, Zhou H, Xu Y, Zhang A, Zhang N iScience. 2020 Feb 21;23(2):100857. doi: 10.1016/j.isci.2020.100857. Epub 2020, Jan 21. PMID:32058968[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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