4ASF

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

Summary for 4ASF

• Entry DOI: 10.2210/pdb4asf/pdb
• Related: 4AS9 4ASA 4ASB 4ASG
• Descriptor: ATP-DEPENDENT MOLECULAR CHAPERONE HSP82, (8S,9R,13R,14S,16R)-21-(furan-2-yl)-13-hydroxy-8,14,19-trimethoxy-16-methyl-4,10,12-trimethylidene-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),18-dien-9-yl carbamate, NICKEL (II) ION, ... (4 entities in total)
• Functional Keywords: inhibition, ansamycin, chaperone
• Biological source: SACCHAROMYCES CEREVISIAE (BAKER'S YEAST)
• Total number of polymer chains: 1
• Total formula weight: 25676.17

Authors

Roe, S.M.,Prodromou, C. (deposition date: 2012-05-01, release date: 2013-04-03, Last modification date: 2024-05-01)

Primary citation

Kitson, R.R.,Chang, C.H.,Xiong, R.,Williams, H.E.,Davis, A.L.,Lewis, W.,Dehn, D.L.,Siegel, D.,Roe, S.M.,Prodromou, C.,Ross, D.,Moody, C.J.
Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90.
Nat Chem, 5:307-314, 2013

PubMed Abstract: 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.

PubMed: 23511419
DOI: 10.1038/nchem.1596

Experimental method

X-RAY DIFFRACTION (2.6 Å)