The Role of Protein Dynamics in β-lactamase Resistance Proteins
The introduction of β-lactam antibiotics to our healthcare repertoire is one of the greatest innovations of the 20th century. 1 These molecules are largely responsible for the increase in expected lifespan as they render once life-threatening bacterial infections easily curable. They elicit their effect through inhibiting Penicillin Binding Proteins (PBPs) as mimics of the D-ala-D-ala substrate the PBPs are responsible for cross-linking in peptidoglycan synthesis of the bacterial cell wall. Antibiotic resistance to β-lactams occurs via many different mechanisms. This dissertation focuses on β-lactamases and a protein associated with signaling for the production of β-lactamases by antibiotic resistance bacteria.
Much of our knowledge about β-lactamase resistance proteins has come from X-ray crystallography studies. 2-7 Two proteins in which crystal structures are available are the extracellular sensor domain of the signaling protein BlaR1 (BlaRS) 6from gram-positive Staphylococcus aureus and the class D β-lactamase OXA-242 from the gram-negative Acinetobacter baumannii. While these studies have provided us with a solid understanding of how these proteins work, these structures largely ignore information about the mobility and dynamics of the protein. This gap in knowledge begs for further exploration into characterizing the dynamics of regions implicated in both binding and hydrolysis of β-lactams.
Nuclear Magnetic Resonance (NMR) is the premier method to determine the site-specific dynamics of proteins. This work focuses on the characterization of the backbone dynamics of BlaRS, OXA-24/40, and OXA-160 using primarily reduced spectral density mapping. The structure equals function paradigm has dominated biochemical thinking since the advent of structural biology. However, this ideology has largely assumed ONE/THE structure equals function. This thesis highlights how protein dynamics, or the structural ensemble of a protein, ultimately shapes a proteins function.
History
Date Created
2017-04-12Date Modified
2018-10-25Defense Date
2017-04-05Research Director(s)
Jeff PengDegree
- Doctor of Philosophy
Degree Level
- Doctoral Dissertation
Program Name
- Chemistry and Biochemistry