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Title page for ETD etd-01222006-213113


Type of Document Dissertation
Author Bilder, Patrick Wallace
Author's Email Address bilderpw@lsu.edu
URN etd-01222006-213113
Title The structural diversity of metal binding sites in bacterial metalloproteins: the disordered iron-binding coil of iron-sulfur cluster protein and the stable zinc ribbon motif of the carboxyltransferase subunit of acetyl-coa carboxylase
Degree PhD
Department Biochemistry
Advisory Committee
Advisor Name Title
Dr. Richard Armstrong Committee Chair
Dr. David Ong Committee Member
Dr. Fred Guengerich Committee Member
Dr. Gerald Stubbs Committee Member
Dr. Marcia Newcomer Committee Member
Keywords
  • Metalloproteins -- Structure
  • Iron-sulfur proteins
  • Antibacterial agents -- Development
  • acetyl-CoA
  • carboxyltransferase
  • iron-sulfur cluster
  • Bacterial proteins -- Structure
  • Acetylcoenzyme A
Date of Defense 2005-09-23
Availability unrestricted
Abstract
This dissertation describes the crystal structures of two distinct metal-binding proteins: Escherichia coli Iron-sulfur cluster protein A and the carboxyltransferase subunit of the acetyl-coA carboxylase enzymes from Staphylococcus aureus and Escherichia coli.

Iron-sulfur cluster protein A (IscA) belongs to an ancient family of proteins responsible for iron-sulfur cluster assembly in essential metabolic pathways preserved throughout evolution. The crystal structure of Escherichia coli IscA reveals a novel fold in which mixed beta-sheets form a compact alpha-beta sandwich domain. In contrast to the highly mobile secondary structural elements within the bacterial Fe-S scaffold protein IscU, a protein which is thought to have a similar function, the great majority of the amino acids which are conserved in IscA homologues are located in elements which constitute a well-ordered fold. However, the 10-residue C-terminal tail segment which contains two invariant cysteines critical for the Fe-S binding function of IscA is not ordered. In addition, the crystal packing reveals a helical assembly which is constructed from two possible tetrameric oligomers of IscA.

The rates of severe, multi-drug resistant bacterial infections, including those caused by pathogens previously confined to the hospital setting, have increased dramatically in both hospital and community populations. Acetyl-coA carboxylase is a central metabolic enzyme that catalyzes the committed step in fatty acid biosynthesis: biotin-dependent conversion of acetyl-coA to malonyl-coA. This work presents the structures of the bacterial carboxyltransferase subunits from two prevalent nosocomial pathogens, Staphylococcus aureus and Escherichia coli. Both structures reveal a small, independent zinc-binding domain that appears to shield the active site during the catalytic process. The zinc domain of bacterial carboxyltransferase, which lacks a complement in the primary sequence or structure of the eukaryotic homologue, is a feature that yields promise for the structure-based design and development of new, selective antimicrobial classes.

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