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. alpha/beta-Tubulin and the molecular chaperone Hsp90 have essential, non-overlapping roles in the life of eukaryotic cells. Both proteins bind and hydrolyze nucleoside triphosphates (GTP for tubulin, ATP for HSP90), and adopt multiple conformations as part of their functional cycle. Recent crystallographic results from the Agard lab have provided new insights into the role of conformational change in these proteins. We determined the structure of gamma-tubulin bound to GTP. Surprisingly, the conformation we observed was essentially identical to what was thought to be the GDP-bound conformation of the closely related alpha/beta-tubulin. Our structure of gamma-tubulin (together with biochemical data) suggests that conformational switching in tubulins is largely independent of nucleotide state. We also determined two structures of the E. coli Hsp90 homolog, HtpG, revealing dramatically different conformations that likely represent important functional states. Small angle X-ray scattering (SAXS) is the highest resolution solution technique capable of reporting on the conformational state of molecular assemblies, and is providing unique structural insight into conformational changes in these proteins. In particular, studying how (or whether) the conformations of these two different proteins respond to nucleotide state is an essential first step in formulating a meaningful mechanistic understanding of their function.
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