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



 
 



Wim Hol
Professor of Biochemistry and Biological Structure
Adjunct Professor of Pharmacology and Bioengineering


PhD 1971, University of Groningen, The Netherlands

Phone: 206.685.7044
Fax: 206.685.7002
wghol@u.washington.edu



Honors
  • 2006 Honorary Doctorate, University of Ghent, Belgium
  • 2004 Honorary Member, Indian Biophysical Society
  • 2004 Chancellor's Distinguished Lecturer, Louisiana State University
  • 2003 C.V. Raman Visiting Professorship, University of Madras, India
  • 2002 Bridget Ogilvie Lecturer, University of Dundee, Scotland
  • 2001 Director, Structural Genomics of Pathogenic Protozoa (SGPP) - NIGMS
  • 1992 Elected Member Royal Dutch Academy of Sciences (KNAW)
  • 1991 Keilin Medal, Biochemical Society, United Kingdom
  • 1989 President, International Symposium, "Prospects in Protein Engineering," Groningen, The Netherlands
  • 1988 Director, "Crystallography of Molecular Biology Course", International School of Crystallography, Erice, Italy
  • 1984 Elected Member European Molecular Biology Organization (EMBO)
  • 1978 Center of Excellence Award, Dutch Foundation for Chemical Research
  • 1978 Gold Medal, Royal Dutch Chemical Society
  • 1976 Z.W.O. Fellowship Award for a year research at UCSD


Research

Research in Dr. Hol's group is multi-disciplinary and directed towards the structure determination of exciting protein molecules as a starting point for understanding the way they function and resolving the intricacies of their often miraculous architecture. Designing new inhibitors that can be further developed into drugs, in particular for the treatment of infectious tropical diseases.

The studies in the last ten years have focused on unraveling the crystal structures of key proteins from major tropical pathogens in parallel with structure-based development of inhibitors of these proteins. Examples are:

  • We have made good progress in deciphering the mode of action of cholera toxin and developing high affinity receptor binding antagonists. The structure of the fully activated form of the toxin, in complex with the human G-protein ARF6, has also been obtained recently. Ongoing studies are aimed at understanding additional interactions of the toxin with human proteins.
  • Structures of five proteins from the sophisticated Type II Secretion System of Vibrio cholerae, which translocates cholera toxin across the outer membrane, have been unraveled in recent years. These are actually only initial steps in understanding the mode of action of this fascinating, two-membrane-spanning, molecular machinery.
  • The intriguing RNA-editing editosome of the sleeping sickness parasite Trypanosoma brucei is able to incorporate dozens of nucleotides into immature mRNAs, resulting in mature messages which are sometimes twice the size of the starting mRNA. The three-dimensional structures of two editosome key enzymes have recently been solved at high resolution revealing fully their nucleotide binding modes. Structure determinations of multiple editosome sub-complexes and complexes with RNA are currently being undertaken.
  • Another most unusual feature of Trypanosoma brucei and related tropical pathogens is the presence of "glycosomes", unique organelles that are critical for energy generation in the bloodstream form of the sleeping sickness parasites. We are studying the "peroxins", proteins responsible for the biogenisis of these essential organelles.
  • The major human malaria parasites Plasmodium falciparum and P. vivax are able to enter human liver cells as well as erythrocytes. The proteins involved in the “invasion machinery” are only just being discovered. We have solved the three-dimensional structure of a key interaction between two proteins of this cell invasion machinery. These are obviously important drug targets for new anti-malarials. Studies on other critical components of this dynamic macromolecular machinery are under way.
  • Two key DNA regulators of Mycobacterium tuberculosis have been caught in the act of binding DNA, which is exploited for the design of small-molecule deregulators of these regulators. One of these regulators shows totally unexpected large variations in tertiary and quaternary structure during its course of action.

Several contributions have also been made to the development of methods in protein crystallography. Most recently these have been made largely within the framework of the Structural Genomics of Pathogenic Protozoa (SGPP) Consortium that has expressed thousands of genes from trypanosomatid and Plasmodium species, purified hundreds of proteins from these pathogens, and solved dozens of crystal structures. Progress can be seen on the SGPP website. This project is being continued as the Medical Structural Genomics of Pathogenic Protozoa (MSGPP) Program Project.

Mode of activation of Cholera Toxin by the human G-protein ARF6

Schematic of the Type II Secretion System of Cholera Toxin (with structures solved indicated)

Two structures of key enzymes from the RNA editing Editosome

The activated Iron-redependent regulator (IDER) from Mycobacterium tuberculosis in complex with DNA

Selected Publications

"Structure of the Plasmodium MTIP-MyoA complex, a key component of the malaria parasite invasion motor." Bosch, J., Turley, S., Daly, T. M., Bogh, S. M., M.L, V., Roach, C., Zhou, N., Morrisey, J. M., Vaidya, A. B., Bergman, L. W. & Hol, W. G. J. Proc. Natl. Acad. Sci. USA 103, 4852-4857 (2006).

"Structural basis for UTP specificity of RNA editing TUTases from Trypanosoma brucei." Deng, J., Lewis Ernst, N., Turley, S., Stuart, K. & Hol, W. G. J. EMBO J 24, 4007-4017 (2005).

"Structural Basis for the Activation of Cholera Toxin by Human ARF6-GTP." O'Neal, C. J., Jobling, M. G., Holmes, R. K. & Hol, W. G. J. Science 309, 1093-1096 (2005).

"The crystal structure of the periplasmic domain of the type II secretion system protein EpsM from Vibrio cholerae: the simplest version of the ferredoxin fold." Abendroth, J., Rice, A. E., McLuskey, K., Bagdasarian, M. & Hol, W. G. J. J. Mol. Biol. 338, 585-596 (2004).

"High Resolution Crystal Structure of an Editosome Enzyme from Trypanosoma brucei: RNA Editing ligase I." Deng, J., Schnaufer, A., Salavati, R., Stuart, K. & Hol, W. G. J. J Mol Biol 343, 601-613 (2004).

"The 1.6 Å Crystal Structure of the Novel Class Of Chaperones Represented by E.coli Hsp31 Reveals a Putative Catalytic Triad." Quigley, P. M., Korotkov, K., Baneyx, F. & Hol, W. G. J. Proc. Natl. Acad. Sci. USA 100, 3137-3142 (2003).

"The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding." Martinez, S. E., Glavas, N. A., Tang, X.-B., Turley, S., Hol, W. G. J. & Beavo, J. A. PNAS 99, 13260-13265 (2002).

"Drugs against Tropical Protozoan Parasites: Target Selection, Structural Biology and Rational Medical Chemistry." Gelb, M. H. & Hol, W. G. J. Science 297, 343-344 (2002).

"Solution and Crystallographic Studies of Branched Multivalent Ligands that Inhibit the Receptor-Binding Process of Cholera Toxin." Zhang, Z., Merritt, E. A., Ahn, M., Roach, C., Hou, Z., Verlinde, C. L. M. J., Hol, W. G. J. & Fan, E. J. Am. Chem. Soc. 124, 12991-12998 (2002).

"Structure-based design of sub-micromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase." Aronov, A. M., Suresh, S., Buckner, F. S., van Voorhis, W. C., Verlinde, C. L. M. J., Hol, W. G. J. & Gelb, M. H. Proc. Natl. Acad. Sci. USA 96, 4273-4278 (1999).

"Principles of quasi-equivalence and Euclidean geometry govern the assembly of cubic and dodecahedral cores of pyruvate dehydrogenase complexes." Izard, T., Ævarsson, A., Allen, M. D., Westphal, A. H., Perham, R. N., de Kok, A. & Hol, W. G. J. Proc. Natl. Acad. Sci. USA 96, 1240-1245 (1999).

"A model for the mechanism of human topoisomerase I." Stewart, L., Redinbo, M. R., Qiu, X., Hol, W. G. J. & Champoux, J. J. Science 279, 1534-1541 (1998).

"Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA." Redinbo, M. R., Stewart, L., Kuhn, P., Champoux, J. J. & Hol, W. G. J Science 279, 1504-1513 (1998).

"Synergistic effects of substrate-induced conformational changes in the activation of phosphoglycerate kinase." Bernstein, B. E., Michels, P. A. M. & Hol, W. G. J. Nature 385, 275-278 (1997).

"Structure of the heat shock protein chaperonin-10 of Mycobacterium leprae." Mande, S., C., Mehra, F., Bloom, B. R. & Hol, W. G. J. Science 271, 203-207 (1996).

"The intact and cleaved human antithrombin III complex as a model for serpin-proteinase interactions." Schreuder, H. A., de Boer, B., Dijkema, R., Mulders, J., Theunissen, H. J. M., Grootenhuis, P. D. J. & Hol, W. G. J. Nature Structural Biology 1, 48-54 (1994).

"Atomic structure of the cubic core of the pyruvate dehydrogenase multi-enzyme complex." Mattevi, A., Obmolova, G., Schulze, G., Kalk, K. H., Westphal, A., de Kok, A. & Hol, W. G. J. Science 255, 1544-1550 (1992).

"Crystal structure of a cholera toxin-related heat-labile enterotoxin from E. coli." Sixma, T. K., Pronk, S. E., Kalk, K. H., Wartna, E. S., van Zanten, B. A. M., Witholt, B. & Hol, W. G. J. Nature 351, 371-377 (1991).

"Inclusion of thermal motion in crystallographic structures by restrained molecular dynamics." Gros, P., van Gunsteren, W. F. & Hol, W. G. J. Science 249, 1149-1152 (1990).

"Protein crystallography and computer graphics - toward rational drug design." Hol, W. G. J. Angewandte Chemie 25, 767-778 (1986).

"3.2 Å structure of the copper-containing, oxygen-carrying protein Panulirus interruptus hemocyanin." Gaykema, W. P. J., Hol, W. G. J., Vereijken, J. M., Soeter, N. M., Bak, H. J. & Beintema, J. J. Nature 309, 23-29 (1984).

"The α-helix dipole and the properties of proteins." Hol, W. G., van Duijnen, P. T. & Berendsen, H. J. C. Nature 273, 443-446 (1978).