Sandbox chaperones: Difference between revisions
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[[Image:Hsp90.jpg|thumb|Conformational changes of Hsp90<ref name='Goodsell'/>]] | [[Image:Hsp90.jpg|thumb|Conformational changes of Hsp90<ref name='Goodsell'/>]] | ||
The inactive form of Hsp90 is open, but binding of ATP causes the molecule to close into the active form. The N-terminal domain is the cite of the ATP binding pocket. Amino acids Leu34, Asn37, Asp79, Asn92, Lys98, Gly121, and Phe124 are in the N-terminal domain and are directly involved in ATP binding. Mg2+ is also present and involved in electrostatic bonding interactions with ATP. This results in a high-affinity ATP-binding site. Hsp90 binds ATP when in the open | The inactive form of Hsp90 is open, but binding of ATP causes the molecule to close into the active form. The N-terminal domain is the cite of the ATP binding pocket. Amino acids Leu34, Asn37, Asp79, Asn92, Lys98, Gly121, and Phe124 are in the N-terminal domain and are directly involved in ATP binding. Mg2+ is also present and involved in electrostatic bonding interactions with ATP. This results in a high-affinity ATP-binding site. Hsp90 binds ATP when in the open/inactive conformation and then cleaves the ATP into ADP to drive the conformational change into the closed/active form.<ref>Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW, Pearl LH (July 1997). "Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone". Cell 90 (1): 65–75. doi:10.1016/S0092-8674(00)80314-1. PMID 9230303.</ref> | ||
The protein binding domain is in the C-terminus. Hydrophobic residues in the C-terminus are exposed while the dimer is in the open conformation, allowing unfolded and misfolded client proteins to bind. When the N-terminal domain hydrolyzes ATP and drives | The protein binding domain is in the C-terminus. Hydrophobic residues in the C-terminus are exposed while the dimer is in the open conformation, allowing unfolded and misfolded client proteins to bind. When the N-terminal domain hydrolyzes ATP and drives the confirmation change the C-terminal domain clamps down on the client protein.<ref>Grenert JP, Sullivan WP, Fadden P, Haystead TA, Clark J, Mimnaugh E, Krutzsch H, Ochel HJ, Schulte TW, Sausville E, Neckers LM, Toft DO (September 1997). "The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation". J. Biol. Chem. 272 (38): 23843–50. doi:10.1074/jbc.272.38.23843. PMID 9295332.</ref> | ||
== Disease == | == Disease == | ||
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Because many client proteins of the chaperone protein Hsp90 are involved in cellular growth, inhibition of the ATPase activity of Hsp90 is a potential strategy for the treatment of cancers. | Because many client proteins of the chaperone protein Hsp90 are involved in cellular growth, inhibition of the ATPase activity of Hsp90 is a potential strategy for the treatment of cancers. | ||
Geldanamycin is a natural product made by Streptomyces bacteria that blocks the binding of ATP to Hsp90 | Geldanamycin is a natural product made by Streptomyces bacteria that blocks the binding of ATP to Hsp90. This freezes the large conformational change needed for function and causes complexes of Hsp90 and misfolded proteins to accumulate in the cytoplasm. These accumulated proteins are then targeted for degredation by the ubiquitin/proteosome system, which ultimately leads to cell death as a result of corrupted growth controlling signaling pathways. Unfortunately, geldanamycin is too toxic to normal body cells for use as an anticancer drug.<ref name='Goodsell'/> | ||
However, less toxic compounds with the same mechanism have been developed. A ligand called PU3 is a purine based inhibitor that has been developed using human Hsp90 protein 1UYM for the potential purpose as an anticancer drug targeted at HSP90 proteins. PU3 tightly binds the ATP binding site of 1UYM and causes downregulation on it's client proteins. This results in misfolded proteins accumulating in the cell and eventual cell death. <ref>DOI: 10.1016/j.chembiol.2004.03.033</ref> | However, less toxic compounds with the same mechanism have been developed. A ligand called PU3 is a purine based inhibitor that has been developed using human Hsp90 protein 1UYM for the potential purpose as an anticancer drug targeted at HSP90 proteins. PU3 tightly binds the ATP binding site of 1UYM and causes downregulation on it's client proteins. This results in misfolded proteins accumulating in the cell and eventual cell death. <ref>DOI: 10.1016/j.chembiol.2004.03.033</ref> | ||
It is important to note that although | It is important to note that although Hsp90 is essential in normal cells to aid in general protein maintenance, cancer cells rely more heavily on Hsp90 and therefore respond more strongly to downregulation. Therefore Hsp90 inhibitors are more detrimental to cancer cells than normal cells.<ref name='Goodsell'/> | ||
== References == | == References == | ||
<references/> | <references/> | ||
