Structural highlights
Function
HSP82_YEAST Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. The nucleotide-free form of the dimer is found in an open conformation in which the N-termini are not dimerized and the complex is ready for client protein binding. Binding of ATP induces large conformational changes, resulting in the formation of a ring-like closed structure in which the N-terminal domains associate intramolecularly with the middle domain and also dimerize with each other, stimulating their intrinsic ATPase activity and acting as a clamp on the substrate. Finally, ATP hydrolysis results in the release of the substrate. 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. Required for growth at high temperatures.[1]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
A series of benzo-macrolactones of varying ring size and conformation has been prepared by chemical synthesis and evaluated by structural and biological techniques. Thus, 12- to 16-membered lactones were obtained by concise routes, involving ring-closing metathesis as a key step. In enzyme assays, the 13-, 15-, and 16-membered analogs are good inhibitors, suggesting that they can adopt the required conformation to fit in the ATP-binding site. This was confirmed by cocrystallization of 13-, 14-, and 15-membered lactones with the N-terminal domain of yeast Hsp90, showing that they bind similarly to the "natural" 14-membered radicicol. The most active compounds in the ATPase assays also showed the greatest growth-inhibitory potency in HCT116 human colon cancer cells and the established molecular signature of Hsp90 inhibition, i.e., depletion of client proteins with upregulation of Hsp70.
Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol.,Proisy N, Sharp SY, Boxall K, Connelly S, Roe SM, Prodromou C, Slawin AM, Pearl LH, Workman P, Moody CJ Chem Biol. 2006 Nov;13(11):1203-15. PMID:17114002[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Proisy N, Sharp SY, Boxall K, Connelly S, Roe SM, Prodromou C, Slawin AM, Pearl LH, Workman P, Moody CJ. Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol. Chem Biol. 2006 Nov;13(11):1203-15. PMID:17114002 doi:10.1016/j.chembiol.2006.09.015
- ↑ Proisy N, Sharp SY, Boxall K, Connelly S, Roe SM, Prodromou C, Slawin AM, Pearl LH, Workman P, Moody CJ. Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol. Chem Biol. 2006 Nov;13(11):1203-15. PMID:17114002 doi:10.1016/j.chembiol.2006.09.015
