2wer | pdb_00002wer

YEAST HSP90 N-TERMINAL DOMAIN LI-IV MUTANT WITH RADICICOL

spinqualitylabelsall models 2wer, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2wer is a 2 chain structure with sequence from Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: RDC Related: 1hk7, 1a4h, 1us7, 2bre, 2vwc, 2cg9, 1ah6, 1bgq, 1usv, 2iws, 1amw, 1usu, 2brc, 1zwh, 2weq, 2vw5, 1ah8, 2cgf, 1am1, 2iwu, 2vls, 2cge, 2iwx, 2wep, 2akp, 1zw9 Resources: FirstGlance, OCA, RCSB, PDBsum 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 Heat shock protein 90 (Hsp90) is a promising cancer drug target, as multiple oncogenic proteins are destabilized simultaneously when it loses its activity in tumor cells. Highly selective Hsp90 inhibitors, including the natural antibiotics geldanamycin (GdA) and radicicol (RAD), inactivate this essential molecular chaperone by occupying its nucleotide binding site. Often cancer drug therapy is compromised by the development of resistance, but a resistance to these Hsp90 inhibitors should not arise readily by mutation of those amino acids within Hsp90 that facilitate inhibitor binding, as these are required for the essential ATP binding/ATPase steps of the chaperone cycle and are tightly conserved. Despite this, the Hsp90 of a RAD-producing fungus is shown to possess an unusually low binding affinity for RAD but not GdA. Within its nucleotide binding site a normally conserved leucine is replaced by isoleucine, though the chaperone ATPase activity is not severely affected. Inserted into the Hsp90 of yeast, this conservative leucine to isoleucine substitution recreated this lowered affinity for RAD in vitro. It also generated a substantially enhanced resistance to RAD in vivo. Co-crystal structures reveal that the change to isoleucine is associated with a localized increase in the hydration of an Hsp90-bound RAD but not GdA. To the best of our knowledge, this is the first demonstration that it is possible for Hsp90 inhibitor resistance to arise by subtle alteration to the structure of Hsp90 itself. Structural Basis of the Radicicol Resistance Displayed by a Fungal Hsp90.,Prodromou C, Nuttall JM, Millson SH, Roe SM, Sim TS, Tan D, Workman P, Pearl LH, Piper PW ACS Chem Biol. 2009 Mar 18. PMID:19236053 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Heat Shock Proteins

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