Ethan A Merritt
Research Associate Professor
Biomolecular Structure Center
- 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. One 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
My lab is one of several UW groups interested in using structural genomics to
identify opportunities for drug design targetting parasitic diseases.
The MSGPP (Medical Structural Genomics of Pathogenic Protozoa) Consotium
has successfully identified and characterized several promising target
proteins from these disease organisms.
- Structure-based drug design
One current project is the development of drugs targetting Ca-dependent
Protein Kinases (CDPKs), a class of proteins found in apicomplexan
parasites but not in humans. We have identified very promising nanomolar
CDPK inhibitors that are active against Cryptosporidia and Toxoplasma.
Further work may capitalize on the presence of homologous target proteins
in the malarial parasite (Plasmodia) and in the related protozoan pest
Eimeria. This work is a collaboration with UW groups in the departments
of Chemistry, Global Health, and Medicine.
- Links to further information on these research projects
MSGPP structural genomics project
Synchrotron radiation, X-ray anomalous scattering and MAD phasing
Bacterial Toxins (past project)
Raster3D photorealistic molecular graphics
Refinement, analysis, and validation of atomic resolution protein structures
TLSMD inference of protein dynamics from single crystal structures
- ET Larson, JE Kim, LJ Castaneda, AJ Napuli, Z Zhang, E Fan, FH Zucker, CLMJ Verlinde, FS Buckner, WC Van Voorhis, WGJ Hol, EA Merritt (2011).
Tyrosyl tRNA-synthetase from the eukaryote Leishmania major is monomeric but forms an intrinsically asymmetric pseudo-dimer.
J Mol Biol 409, 159-176.
- EA Merritt, TL Arakaki, R Billespie, AJ Napuli, JE Kim, FS Buckner, EC Van Voorhis, CLMJ Verlinde, E Fan, F Zucker, WGJ Hol (2011).
Crystal structures of three protozoan homologs of tryptophanyl-tRNA synthetase.
Molecular and Biochemical Parasitology 177, 20-28.
- F Zucker, PC Champ, EA Merritt (2010).
Validation of crystallographic models containing TLS or other descriptions of anisotropy.
Acta Cryst. D66, 889-900.
- KK Ojo, ET Larson, KR Keyloun, LJ Castaneda, AE DeRocher, KK Inampudi, JE Kim, T Arakaki, R Murphy, L Zhang, AJ Napuli, DJ Maly, CLMJ Verlinde, FS Buckner, M Parsons, WGJ Hol, EA. Merritt, WC Van Voorhis (2010).
A Unique Variation of the ATP binding site makes Toxoplasma gondii Calcium-Dependent Protein Kinase 1 a drug target for selective kinase inhibitors.
Nature Struct. Molec. Biol. 17, 602-607.
- ET Larson, DG Mudeppa, JR Gillespie, N Mueller, AJ Napuli, JA Arif, J Ross, TL Arakaki, A Lauricella, G DeTitta, J Luft, F Zucker, CLMJ Verlinde, E Fan, WC Van Voorhis, FS Buckner, PK Rathod, WGJ Hol, EA. Merritt (2010).
The Crystal Structure and Activity of a Putative Trypanosomal Nucleoside Phosphorylase Reveal It to be a Homodimeric Uridine Phosphorylase.
J. Molec. Biol. 396, 1244–1259.
- ET Larson, W Deng, BE Krumm, A Napuli, N Mueller, WC Van Voorhis, FS Buckner, E Fan, A Lauricella, G DeTitta, J Luft, F Zucker, WGJ Hol, CLMJ Verlinde, EA Merritt (2008).
Structures of substrate- and inhibitor-bound adenosine deaminase from a human malaria parasite show a dramatic conformational change and shed light on drug selectivity.
J Mol Biol 381, 975-988.
- 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-
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
Acta Cryst D55, 1109-1117.
- EA Merritt & DJ Bacon (1997).
"Raster3D: Photorealistic Molecular Graphics"
Methods in Enzymology 277, 505-524.