Martin Horvath
Associate Professor of Biology
B.S. Brown University
Ph.D. University of Chicago
Martin Horvath's Lab Page
Martin Horvath's PubMed Literature Search
Molecular Biology Program
Biological Chemistry Program
Structural Biology, X-Ray Crystallography
Research
N-methyl-D-aspartate (NMDA) type glutamate receptors (NMDAR)s make possible the cognitive functions of learning and memory in humans. Specific antagonists are critically needed to dissect molecular roles of NMDARs and to block hyperactivity associated with neurological diseases such as Alzheimer's, multiple sclerosis, and neuropathic pain. Newly discovered toxins derived from the venoms of marine snails (Conus and Turridae) may hold the key. These toxins can distinguish among highly related NMDARs, inhibiting one subtype but leaving others functional -- exactly the molecular properties needed for basic neurobiological research tools and pharmacologically useful compounds. We wish to determine the structures of these toxins, both as free compounds and as complexed with relevant portions of NMDA receptors. Together with binding specificity analysis (measured by isothermal titration calorimetry and other solution based methods), these structures will aid in the design of NMDAR-targeted drugs.
NMDAR-targeted toxins. (a) Conantokins are rich in gamma-carboxyglutamatic acid residues (red ovals) and adopt helical structure coupled with calcium ion binding. (b, c) Calcium ions additionally bridge toxin to the cell membrane, which probably aids in locating NMDARs. The current goals are to express ligand-binding domains derived from different NMDAR subtypes (extracellular clam-shell shapes), demonstrate subtype selectivity, and crystallize complexes with toxin.
References
- Vickrey AI, Domyan ET, Horvath MP, Shapiro MD (2015) Convergent Evolution of Head Crests in Two Domesticated Columbids Is Associated with Different Missense Mutations in EphB2. Mol Biol Evol, 32:2657-64
- Platt RJ, Curtice KJ, Twede VD, Watkins M, Gruszczyński P, Bulaj G, Horvath MP, Olivera BM (2014) From molecular phylogeny towards differentiating pharmacology for NMDA receptor subtypes. Toxicon, 81:67-79
- Horvath MP (2011) Structural anatomy of telomere OB proteins. Critical Reviews in Biochemistry & Molecular Biology, 46:409-435
- Zakharova E, Horvath MP, Goldenberg DP (2009) Structure of a serine protease poised to resynthesize a peptide bond. Proc Natl Acad Sci U S A, 106:11034-11039
- Zakharova E, Horvath MP, Goldenberg DP (2008) Functional and structural roles of the Cys14-Cys38 disulfide of bovine pancreatic trypsin inhibitor. J Mol Biol, 382:998-1013
- Horvath MP (2008) Single-stranded nucleic acid-binding proteins, in Protein-Nucleic Acid Interactions: Structural Biology (Rice, P. A., and Correll, C. C., Eds.), pp 91-128, Royal Society of Chemistry, London
- Horvath MP (2008) Evolution of telomere binding proteins, in Origin and Evolution of Telomeres (Tomaska, L., and Nosek, J., Eds.), pp 83-99, Landes Bioscience, Austin, TX
- Hanson WM, Domek GJ, Horvath MP, Goldenberg, DP (2007) Rigidification of a flexible protease inhibitor variant upon binding to trypsin. J Mol Biol, 366:230-243
- Suzuki T, McKenzie M, Ott E, Ilkun O, Horvath MP (2006) DNA binding affinity and sequence permutation preference of the telomere protein from Euplotes crassus. Biochemistry, 45:8628-8638
- Dy CY, Buczek P, Imperial JS, Bulaj G, Horvath, MP (2006) Structure of conkunitzin-S1, a neurotoxin and Kunitz-fold disulfide variant from cone snail. Acta Crystallogr D Biol Crystallogr, 62:980-990
- Buczek P, Horvath MP (2006) Structural reorganization and the cooperative binding of single-stranded telomere DNA in Sterkiella nova. J Biol Chem, 281:40124-40134
- Buczek P, Horvath MP (2006) Thermodynamic characterization of binding Oxytricha nova single strand telomere DNA with the alpha protein N-terminal domain. J Mol Biol, 359:1217-1234
- Buczek P, Orr RS, Pyper SR, Shum M, Kimmel E, Ota I, Gerum SE, Horvath MP (2005) Binding linkage in a telomere DNA-protein complex at the ends of Oxytricha nova chromosomes. Journal of Molecular Biology, 350:938-952
- Horvath, MP, Schweiker, VL, Bevilacqua, JM, Ruggles, JS, and Schultz, SC (1998) Crystal structure of the Oxytricha nova telomere end binding protein complexed with single strand DNA. Cell, 95:963-974
