Martin Horvath

Structural Biology & Biochemistry. My research explores how proteins work, and how molecular interactions establish emergent properties of specificity, allostery, and catalysis. With x-ray crystallography, I obtained structures for DNA enzymes with DNA, including the first structure of a single-stranded DNA-protein complex found at the telomere. With Cryo-EM I aim to build structures for membrane proteins. My expertise helps my colleagues think about biological systems in terms of molecular mechanisms.

 

DNA Repair Enzymes

DNA repair enzymes protect our genome from attack. Think Guardians of the Galaxy, but at the molecular level. We study the structure, mechanism and evolution of base excision repair enzymes, especially MutY in bacteria and its mammalian homolog MYH. MutY belongs to a large family of enzymes that scan the DNA in our cells for potential problems and resolve those before they turn into mutations. In collaboration with Dr. Sheila David (UC Davis) we have puzzled out how MutY stabilizes its transition state and developed a chemical mechanism for this amazing enzyme. In collaboration with Dr. William Brazelton (University of Utah) we are testing whether microbes living at the hydrothermal fields also use MutY as bacteria do at the surface of Earth.

 

Tailocins: Bacterial killing machines

To survive in the competitive space created upon plant colonization, pathogenic bacteria deploy R-type tailocins that resemble the contractile tails of bacteriophages. Made in one bacterium and released through lysis, tailocins efficiently kill closely related competitors, yet avoid killing clonal kin. To elucidate the molecular mechanism of killing specificity, we are applying complex carbohydrate analysis, protein biochemistry, and structural biology. We’ve determined the outer antigen glycan structure for a susceptible strain of P. viridiflava comprising a linear, repeated polymer of L-rhamnose, with a rarely observed 3-N-acetyl modified 3-deoxy-D-fucose as single-residue branches. Recombinantly expressed tail fiber proteins assembled into quaternary structure as directed by co-expressed tail-fiber associated chaperone. Purification of tail fiber protein and the minimal glycan receptor is in progress. An x-ray crystal structure for the glycan-protein complex will illuminate molecular interactions underlying target specificity of the tailocin. We will evaluate dissociation kinetics by examining persistence over time with an innovative microscope adapted for viewing hundreds of molecular complexes at single-molecule resolution while force is applied by centrifugation. The protein-glycan structures and binding studies will train AI models. My vision is to understand the rules for glycan recognition so that we can redirect tailocins to kill novel pathogens as they arise in the environment and in the clinic. Realizing this vision will transform how we control pathogens, protect the food we eat, and save lives that otherwise are at risk because of antibiotic resistance.

Carotenoid Proteins and Eye Health

Carotenoids are fat-soluble pigment molecules, becoming increasingly well-known for their phytochemical properties associated with various health benefits. As potent antioxidants and photoprotective agents, carotenoids have vital structural and diverse functional roles in both plants and humans, especially ocular health. The macula lutea, the region responsible for central vision, is uniquely concentrated with xanthophyll carotenoids. Xanthophylls, lutein and zeaxanthin, have specific binding proteins (StARD3 and GSTP1, respectively) within the macula. The accumulation of meso-zeaxanthin is suspected to be mediated by RPE65 through an isomerization reaction of lutein. Using both a computational and biochemical approach to explore the transport, absorption, and stabilization of carotenoids within the human eye. This project is in collaboration with the Bernstein Lab of the Moran Eye Center.