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 chaperones play central roles in the later stages of client protein maturation and, because these clients moderate key checkpoints in cellular growth and development, are recognized as significant cancer therapeutic targets. Questions at the forefront of the field currently center on the development of inhibitory ligands of high specificity, and the nature of the interaction between the chaperone and its client proteins and accessory factors. We are requesting beam time to study the interaction of the hsp90 family of molecular chaperones with novel small molecule inhibitory ligands and previously uncharacterized macromolecular partners. We have previously determined high resolution crystal structures of intact GRP94 (the endoplasmic recticulum Hsp90), as well as the N- terminal ligand binding domain. Crystals of the N-terminal domain in complex with inhibitory ligands typically diffract to better than 2 ? using synchrotron radiation. Crystals of the intact chaperone diffract to roughly 2.5 ? under favorable conditions. Complexes between the chaperone and macromolecular partners such as the Erad (ER associated degradation) protein are expected to diffract weakly and, because of their small size, are difficult to characterize using home X-ray sources. Our plan is to use CHESS beam time to 1) collect high resolution data from crystals of GRP94-Nterm plus inhibitory ligands, and 2) characterize and collect data from crystals of intact GRP94 in complex with the Erad protein.
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