| Structural highlights
4asg is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | 1a4h, 1ah6, 1ah8, 1am1, 1amw, 1bgq, 1hk7, 1us7, 1usu, 1usv, 1zw9, 1zwh, 2akp, 2brc, 2bre, 2cg9, 2cge, 2cgf, 2iws, 2iwu, 2iwx, 2vw5, 2vwc, 2wep, 2weq, 2wer, 2xd6, 2xx2, 2xx4, 2xx5, 2yga, 2yge, 2ygf, 4as9, 4asa, 4asb, 4asf |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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]
Publication Abstract from PubMed
The benzoquinone ansamycin geldanamycin and its derivatives are inhibitors of heat shock protein Hsp90, an emerging target for novel therapeutic agents both in cancer and in neurodegeneration. However, the toxicity of these compounds to normal cells has been ascribed to reaction with thiol nucleophiles at the quinone 19-position. We reasoned that blocking this position would ameliorate toxicity, and that it might also enforce a favourable conformational switch of the trans-amide group into the cis-form required for protein binding. Here, we report an efficient synthesis of such 19-substituted compounds and realization of our hypotheses. Protein crystallography established that the new compounds bind to Hsp90 with, as expected, a cis-amide conformation. Studies on Hsp90 inhibition in cells demonstrated the molecular signature of Hsp90 inhibitors: decreases in client proteins with compensatory increases in other heat shock proteins in both human breast cancer and dopaminergic neural cells, demonstrating their potential for use in the therapy of cancer or neurodegenerative diseases.
Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90.,Kitson RR, Chang CH, Xiong R, Williams HE, Davis AL, Lewis W, Dehn DL, Siegel D, Roe SM, Prodromou C, Ross D, Moody CJ Nat Chem. 2013 Apr;5(4):307-14. doi: 10.1038/nchem.1596. Epub 2013 Mar 10. PMID:23511419[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Kitson RR, Chang CH, Xiong R, Williams HE, Davis AL, Lewis W, Dehn DL, Siegel D, Roe SM, Prodromou C, Ross D, Moody CJ. Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90. Nat Chem. 2013 Apr;5(4):307-14. doi: 10.1038/nchem.1596. Epub 2013 Mar 10. PMID:23511419 doi:http://dx.doi.org/10.1038/nchem.1596
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