We use a combination of biochemistry, biophysics, and structural biology (cryo-electron microscopy, X-ray crystallography, and molecular dynamics) to understand the atomic-resolution mechanisms by which various pathogens interact with their hosts. Ongoing projects include:
CRESS-DNA viruses:
Structural and functional studies of members of circular, Rep-encoding ssDNA (CRESS DNA) viruses. These viruses infect Archaea and Eukaryotes. The shared characteristics between these viruses are: 1) small circular ssDNA genomes (less than 5,000 nt), 2) few ORFs in the genome (one encoding for a capsid protein and the other for a replicase), and 3) a replicase that exhibits multiple functions necessary for replication of the viral genome. Indeed, it is the replicase that unifies these viruses into a recently proposed virus phylum named Cressdnaviricota. Moreover, homologous replicases are also found in prokaryotes. These replicases are believed to be responsible for bacterial plasmid replication. We use a blend of biochemistry, biophysics, and structural biology (cryo-EM, X-ray crystallography, and molecular dynamics) to study the mechanism by which the prototypical member (Porcine circovirus 2, PCV2) of this phylum infects cells at atomic-resolution. PCV2 infects multiple animal cells, including human cells in culture, and induces immunosuppression in these hosts. It’s ability to infect multiple species and human cells suggests that it is on the precipitous of becoming zoonotic.
Membrane fusion:
Structural and functional studies of membrane fusion between lipopolysaccharides (LPS) and phospholipids (PL). In a collaborative project, we are studying a unique phage that fuses its bacterial PL with the LPS of its Gram-negative host to initiate infection. This unusual system allows for the study of a biochemical process that is poorly understood. Moreover, it allows for the development of tunable nanotherapeutics for delivery antibiotics into selectable strains of Gram-negative bacteria. We use a blend of phage genetics, biochemistry, biophysics, and structural biology (cryo-ET, cryo-EM, and X-ray crystallography).
Antibiotic resistance:
Structural robustness of ribosome functional centers. The ribosome is responsible for protein synthesis (translation) and is thus fundamental component of gene expression. Because of this central role, the ribosome has become the target of most (> 50%) antibiotics. In a collaborative project, we are studying the molecular mechanism of antibiotic resistance via ribosome evolution to better understand how the ribosome can evolve to become antibiotic resistant, and to use this knowledge to develop antibiotics which the ribosome is unable to evade.
Resources
Available to the lab
The facilities below are fully accessible to members of the laboratory
and will be heavily used throughout the research
Institute for Macromolecular Assemblies
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