Department of Biochemistry Box 357350 University of Washington Seattle, WA 98195
 



 
 
 

       
Ethan Merritt         


     Research Associate Professor

     206.543.1421 V
     merritt@u.washington.edu

 

Research

I am pursuing a many-faceted research program for the design of new drugs and vaccines based on the crystallographic study of a remarkable class of bacterial toxins. These toxins include the causative agent of cholera and of E. coli-derived acute dysentery. The detailed views of the receptor-binding and enzymatic sites on these toxins provided through crystallography allow us to design potential inhibitors which bind to the toxins to block their normal activity. These compounds can be developed into candidate drugs through iterative cycles of crystallographic analysis, design, synthesis, and characterization.

I am also broadly interested in developing and applying new technologies and new computational techniques to problems of molecular structure. One focus of my research has been the use of synchrotron radiation to pursue new methods such as MAD phasing for macromolecular x-ray crystallography. Another major effort is to develop new and better computational tools for modelling, analyzing, visualizing and interpreting high-resolution protein structures.

I am a member of the SGPP (Structural Genomics of Pathogenic Protozoa) Consortium, a collaborative effort to build a database of protein structures derived from tropical disease organisms. The overall goal of the structural genomics initiative is to build a structural database containing a representative structure for every genomic DNA sequence family. The specific focus of the SGPP project is on proteins from a set of medically important pathogens. Many of these proteins may prove to be suitable drug-design targets. Technology development is an important component of the SGPP. I am working on hardware and software systems design for high-throughput X-ray crystallography and structure analysis. Component projects include robotics, image recognition, interactive graphics, and the development of validation tools. Also included are data-mining techniques applied to the growing structural database, particular efforts to deduce elements of a protein's function directly from its structure.

Links to further information on these research projects

SGPP structural genomics project
Synchrotron radiation, X-ray anomalous scattering and MAD phasing
Bacterial Toxin Projects
Raster3D photorealistic molecular graphics
Refinement, analysis, and validation of atomic resolution protein structures


Selected Publications

Bagley MC, Dale JW, Merritt EA, Xiong X (2005) Thiopeptide antibiotics. Chem Rev 105, 685-714.

Caruthers J, Zucker F, Worthey E, Myler PJ, Buckner F, Van Voorhuis W, Mehlin C, Boni E, Feist T, Luft J, Gulde S, Lauricella A, Kaluzhniy O, Anderson L, Le Trong I, Holmes MA, Earnest T, Soltis M, Hodgson KO, Hol WG, Merritt EA (2005) Crystal structures and proposed structural/functional classification of three protozoan proteins from the isochorismatase superfamily. Protein Sci 14, 2887-2894.

Painter J, Merritt EA (2005) A molecular viewer for the analysis of TLS rigid-body motion in macromolecules. Acta Crystallogr D Biol Crystallogr 61, 465-471.

Robien MA, Bosch J, Buckner FS, Van Voorhis WC, Worthey EA, Myler P, Mehlin C, Boni EE, Kalyuzhniy O, Anderson L, Lauricella A, Gulde S, Luft JR, Detitta G, Caruthers JM, Hodgson KO, Soltis M, Zucker F, Verlinde CL, Merritt EA, Schoenfeld LW, Hol WG (2005) Crystal structure of glyceraldehyde-3-phosphate dehydrogenase from Plasmodium falciparum at 2.25 A resolution reveals intriguing extra electron density in the active site. Proteins.

Bagley MC, Merritt EA (2004) The stereochemistry of micrococcin P1 reinvestigated. J Antibiot (Tokyo) 57, 829-831.

Fan E, O'Neal CJ, Mitchell DD, Robien MA, Zhang Z, Pickens JC, Tan XJ, Korotkov K, Roach C, Krumm B, Verlinde CL, Merritt EA, Hol WG (2004) Structural biology and structure-based inhibitor design of cholera toxin and heat-labile enterotoxin. Int J Med Microbiol 294, 217-223.

Fan E, Merritt EA (2002) Combating infectious diseases through multivalent design. Curr Drug Targets Infect Disord 2, 161-167.

Hirst TR, Fraser S, Soriani M, Aman AT, de HL, Hearn A, Merritt E (2002) New insights into the structure-function relationships and therapeutic applications of cholera-like enterotoxins. Int J Med Microbiol 291, 531-535.

Merritt EA, Zhang Z, Pickens JC, Ahn M, Hol WG, Fan E (2002) Characterization and crystal structure of a high-affinity pentavalent receptor-binding inhibitor for cholera toxin and E. coli heat-labile enterotoxin. J Am Chem Soc 124, 8818-8824.

Pickens JC, Merritt EA, Ahn M, Verlinde CL, Hol WG, Fan E (2002) Anchor-based design of improved cholera toxin and E. coli heat-labile enterotoxin receptor binding antagonists that display multiple binding modes. Chem Biol 9, 215-224.

Zhang Z, Merritt EA, Ahn M, Roach C, Hou Z, Verlinde CL, Hol WG, Fan E (2002) Solution and crystallographic studies of branched multivalent ligands that inhibit the receptor-binding of cholera toxin. J Am Chem Soc 124, 12991-12998.

Aman AT, Fraser S, Merritt EA, Rodigherio C, Kenny M, Ahn M, Hol WG, Williams NA, Lencer WI, Hirst TR (2001) A mutant cholera toxin B subunit that binds GM1- ganglioside but lacks immunomodulatory or toxic activity. Proc Natl Acad Sci U S A 98, 8536-8541.

Fan E, Merritt EA, Zhang Z, Pickens JC, Roach C, Ahn M, Hol WG (2001) Exploration of the GM1 receptor-binding site of heat-labile enterotoxin and cholera toxin by phenyl-ring-containing galactose derivatives. Acta Crystallogr D Biol Crystallogr 57, 201-212.

Fan E, Merritt EA, Verlinde CL, Hol WG (2000) AB(5) toxins: structures and inhibitor design. Curr Opin Struct Biol 10, 680-686.

Minke WE, Pickens J, Merritt EA, Fan E, Verlinde CL, Hol WG (2000) Structure of m-carboxyphenyl-alpha-D-galactopyranoside complexed to heat-labile enterotoxin at 1.3 A resolution: surprising variations in ligand-binding modes. Acta Crystallogr D Biol Crystallogr 56 (Pt 7), 795-804.