2IWU

Analogues of radicicol bound to the ATP-binding site of Hsp90

Summary for 2IWU

• Entry DOI: 10.2210/pdb2iwu/pdb
• Related: 1A4H 1AH6 1AH8 1AM1 1AMW 1BGQ 1HK7 1US7 1USU 1USV 1ZWH 2AKP 2BRC 2BRE 2CG9 2CGE 2CGF 2IWS 2IWX
• Descriptor: ATP-DEPENDENT MOLECULAR CHAPERONE HSP82, (5E)-12-CHLORO-13,15-DIHYDROXY-4,7,8,9-TETRAHYDRO-2-BENZOXACYCLOTRIDECINE-1,10(3H,11H)-DIONE (3 entities in total)
• Functional Keywords: inhibitor, chaperone, heat shock, atp-binding, multigene family, nucleotide-binding
• Biological source: SACCHAROMYCES CEREVISIAE (BAKER'S YEAST)
• Cellular location: Cytoplasm: P02829
• Total number of polymer chains: 1
• Total formula weight: 24533.34

Authors

Roe, S.M.,Prodromou, C.,Pearl, L.H. (deposition date: 2006-07-04, release date: 2006-11-30, Last modification date: 2023-12-13)

Primary citation

Proisy, N.,Sharp, S.Y.,Boxall, K.,Connelly, S.,Roe, S.M.,Prodromou, C.,Slawin, A.M.Z.,Pearl, L.H.,Workman, P.,Moody, C.J.
Inhibition of Hsp90 with Synthetic Macrolactones: Synthesis and Structural and Biological Evaluation of Ring and Conformational Analogs of Radicicol.
Chem.Biol., 13:1203-, 2006

PubMed Abstract: 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.

PubMed: 17114002
DOI: 10.1016/J.CHEMBIOL.2006.09.015

Experimental method

X-RAY DIFFRACTION (2.8 Å)