The C-terminal half of heat shock protein 90 represents a second site for pharmacologic intervention in chaperone function.
The molecular chaperone heat shock protein 90 (Hsp90) is required for stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer cell growth and/or survival. It is also critical for the function of many normally expressed proteins, including protein kinases, steroid receptors and other transcription factors, and it may protect the cell from incapacitating or deleterious mutations. The recent identification of a nucleotide binding pocket within the first 220 amino acids of the protein, together with the discovery that at least two structurally distinct classes of antibiotic can replace nucleotide at this site and alter chaperone activity, has deservedly focused attention on Hsp90's aminoterminus as an important regulator of function. However, data continue to accumulate pointing to the C-terminal half of the chaperone as an equally important regulator of activity, and small molecules that bind to this portion of Hsp90 have been identified.
Marcu
Monica G
MG
Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Rockville, MD 20850, USA.
Neckers
Leonard M
LM
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors* / Q000502:physiology*
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D000251:Adenosine Triphosphatases