This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This is a proposal describing research into multi-domain and multi-protein assemblies under study in our labs. The Gulick lab is investigating the structural arrangement of non-ribosomal peptide synthetases (NRPSs). These modular proteins catalyze the synthesis of peptides antibiotics and peptide siderophores using amino acid and peptide intermediates that are covalently bound to a carrier domain that delivers substrates to the necessary catalytic domains in a coordinated fashion. The choreography of this assembly line synthesis is being investigated through biochemical studies and structural investigations of multi-domain proteins trapped in catalytically relevant states. Additional projects investigate auxiliary proteins that function with NRPS enzymes in the synthesis of natural products. The Gewirth lab studies the multi-domain HSP90 class of molecular chaperones. Questions at the forefront of the field currently center on the development of inhibitory ligands of high specificity, as well as understanding the mechanistic differences between cytoplasmic Hsp90 and GRP94. We are using x-ray crystallography in combination with biochemical and cell-based assays to study the interaction of the hsp90 family of molecular chaperones with novel small molecule inhibitory ligands.
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