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Structure/Function Studies of Yersinia pestis Metal Transport Systems
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Dissertation
Structure/Function Studies of Yersinia pestis Metal Transport Systems
2017
Overview
The largest market sector of the global antibiotics industry is on the verge of becoming obsolete because the incidence of ?-lactam antibiotic resistance in the clinic continues to rise. Therefore, we are in dire need of new therapeutics to address the increasing threat of antibiotic resistance. Novel targets that could lead to a new drug class are ABC (ATP-binding cassette) importers, which are only found in bacteria. The substrate-binding protein (SBP) components of these transporters present an intriguing subject of study because of their abundance in the cell and potential roles in infection. As a contribution to the scholarship of SBP structural biology, this dissertation presents atomic structures of two SBPs involved in iron transport as well as an innovative method for obtaining the apo (substrate-free) forms of SBPs that directly bind metal atoms. Using a biophysical approach including X-ray fluorescence and anomalous X-ray scattering, I demonstrate how YfeA, a polyspecific SBP and Yersinia pestis virulence factor, can use a single canonical substrate-binding site to bind iron, manganese, or zinc atoms. Using a combination of structural analyses and substrate docking simulations, I argue that apo YiuA, a Y. pestis SBP with unknown substrate, is designed to bind a chelate complex and may bind multiple xenosiderophores. In addition, I present evidence that cell fractionation can successfully extract apo YfeA from the periplasm of Escherichia coli when YfeA is exposed to the Yfe transporter. Time-resolved crystallographic experiments reveal that apo YfeA can spontaneously revert to the holo (substrate-bound) YfeA form while still crystallized. Based on the structural changes that occur between apo and holo forms, I argue that YfeA uses a trap door mechanism for substrate transfer to the Yfe transporter. This study simultaneously elucidates a new fundamental mechanism (trap door mechanism) that is distinct from the standard (Venus flytrap mechanism) that currently describes SBP substrate transfer, a method for obtaining apo Cluster A-1 SBPs without artificial intervention such as mutagenesis, partial denaturation, or chelation, and expansion of the SBP structural biology knowledge base.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9780355772166, 0355772167
