4asa

The structure of modified benzoquinone ansamycins bound to yeast N- terminal Hsp90

spinqualitylabelsall models 4asa, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4asa is a 1 chain structure with sequence from Atcc 18824. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 59C, CL 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, 4asb, 4asf, 4asg 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Heat Shock Proteins

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