Ethan A Merritt

methods development in protein crystallography

I am broadly interested in developing and applying new technologies and new computational techniques to problems of molecular structure. I have worked on beamline design, robotics, and the creation of new and better computational tools for modelling, analyzing, visualizing and interpreting protein structures. A recent ongoing project is the use of TLS models to detect and describe local flexibility in proteins. These models are applicable to protein-protein docking and to model ligand binding at a flexible binding site.

structural genomics

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, in particular efforts to deduce elements of a protein's function directly from its structure.

structure-based drug design

Several of my research projects support structure-based drug design targetting infectious disease organisms. We use crystallography to determine the 3-dimensional structure of possible drug targets drawn from the genomes of eukaryotic pathogens. These are then used as a starting point for crystallographic screening against libraries of chemical fragments, and computational screening against libraries of drug-like molecules. These compounds can be developed into candidate lead compounds for drug design through an iterative cycle of crystallographic analysis / design / synthesis / characterization

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

• T Arakaki, H Neely, E Boni, N Mueller, FS Buckner, WC Van Voorhis, A Lauricella, G DeTitta, J Luft, WGJ Hol, EA Merritt (2007). "The structure of Plasmodium vivax phosphatidylethanolamine-binding protein suggests a functional motif containing a lef-handed helix." Acta Cryst F63, 178-182.
• J Painter & EA Merritt (2006). "Optimal description of a protein structure in terms of multiple groups undergoing TLS motion". Acta Cryst D62, 439-450.
• J Bosch, MA Robien, C Mehlin, E Boni, A Riechers, FS Buckner, WC Van Voorhis, PJ Myler, EA Worthey, G DeTitta, JR Luft, A Lauricella, S Gulde, LA Anderson, O Kalyuzhniy, HM Neely, J Ross, TN Earnest, M Soltis, L Schoenfeld, F Zucker, EA Merritt, E Fan, CLMJ Verlinde, & WGJ Hol (2006). "Using Fragment Cocktail Crystallography To Assist Inhibitor Design of Trypanosoma brucei Nucleoside 2- Deoxyribosyltransferase". J. Med. Chem. 49, 5939-5946.
• J Caruthers, et al., EA Merritt (2005). "Crystal structures and proposed structural/functional classification of three protozoan proteins from the isochorismatase superfamily". Protein Science 14, 2887-2984.
• J Painter & EA Merritt (2005). "A molecular viewer for the analysis of TLS rigid body motion in macromolecules". Acta Cryst D61, 465-471.
• J Painter & EA Merritt (2004). "mmLib Python toolkit for manipulating annotated structural models of biological macromolecules". J. Appl. Cryst. 37, 174-178.
• EA Merritt, Z Zhang, JC Pickens, M Ahn, WGJ Hol, & E Fan (2002). "Characterization and Crystal Structure of a High-Affinity Pentavalent Receptor-Binding Inhibitor for Cholera Toxin and E. coli Heat-Labile Enterotoxin". JACS 124, 8818-8824.
• E Fan, EA Merritt, CLMJ Verlinde & WGJ Hol (2000). "AB₅ toxins: structures and inhibitor design". Current Opinion in Structural Biology 10, 680-686.
• EA Merritt (1999). Comparing Anisotropic Displacement Parameters in Protein Structures. Acta Cryst D55, 1997-2004.
• EA Merritt (1999). Expanding the model: anisotropic displacement parameters in protein structure refinement. Acta Cryst D55, 1109-1117.
• EA Merritt & DJ Bacon (1997). "Raster3D: Photorealistic Molecular Graphics" Methods in Enzymology 277, 505-524.
• EA Merritt, S Sarfaty, IK Feil, & WGJ Hol (1997). "Structural foundation for the design of receptor-binding antagonists targeting E. coli heat-labile enterotoxin" Structure 5, 1485-1499.