This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hsp90 is an essential chaperone in eukaryotes that is involved in the maturation of numerous kinases. Because numerous oncogenic kinases rely on Hsp90 for their function, Hsp90 has emerged as a promising target for anti-cancer therapeutics. The design of effective Hsp90 inhibitors would benefit from a molecular understanding of Hsp90 mechanism. Recently, two structures of Hsp90 have been determined both with the C-terminal domain forming a stable dimer. In one structure the N-terminal domain is also dimerized forming a closed state, and in the other structure the N-terminal domain is separated by a large distance (>60 Angstroms). Small-angle X-ray scattering (SAXS) experiments are consistent with a model where ATP-binding shifts Hsp90 from the open to the closed conformation. To determine if the open conformation is involved in kinase maturation, we have engineered Hsp90 with a coiled-coil to hold the N-domain in the closed conformation in the absence of ATP binding. SAXS experiments at APS would provide critical data to determine the conformational states of our engineered Hsp90 molecules both in the presence and absence of ATP. Combined with in vivo studies currently underway to analyze kinase maturation, the SAXS data will provide important insights into a fundamental process in biology and medicine.
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