Postdoc Openings

Heidi Singer hragland at
Tue Apr 4 17:01:18 EST 2000


Howard Hughes Medical Institute & Biomolecular Structure Center
University of Washington

 In the near future several postdoctoral fellowships are available in
our laboratory to work on a number of medically relevant structural
biology projects. The goals of these studies are to unravel mechanisms
of action of proteins and at the same time use the structural
information obtained for the development of potentially useful
therapeutic compounds. The projects are all embedded in exciting
structure-based drug design collaborative networks.

 Most of the projects are aimed to combat major infectious diseases,
while one is also of major importance for cancer. A brief description of
projects is as follows:

1. Structural investigations of the biogenesis of unique organelles,
called glycosomes, in Trypanosomatids which are protozoa responsible for
several of the most important infectious diseases world wide. The
glycosomal matrix proteins are all synthesized in the cytoplasm after
which they are transported into the glycosome via a most unusual and
interesting yet far from completely understood import mechanism. This
process somehow involves almost two dozen different proteins called
"peroxins". The goal of the project is to unravel the structures of the
proteins crucial for this import process, to see how they interact with
the "cargo proteins" and with each other during the translocation of
proteins from the cytoplasm into the glycosome. Structure-based
inhibitor design projects, aiming at discovering selective inhibitors of
this import process, will be initiated immediately once crystal
structures have been elucidated.

2. Structure-based drug design projects focusing on glycosomal proteins
from Trypanosoma brucei and Leishmania species. These are
crystallographic studies in close collaboration with medicinal chemists,
molecular modelers and parasitologists. The aims are (i) to improve the
affinity of very promising inhibitors already developed in the course of
the project, and (ii) to discover and design entirely novel inhibitors
of other target proteins. Excellent expression systems of the target
proteins are available. We are not only focusing in the active site and
co-factor binding sites of enzymes but also on blocking glycosomal
import signals of these glycosomal proteins.

3. Crystallographic investigations on human and malaria topoisomerase I.
Eukaryotic topoisomerases I are remarkable proteins able to relax both
positively and negatively supercoiled DNA by breaking one strand of the
duplex and resealing this broken strand after relaxing the DNA. Several
structures have already been determined in our laboratory of human
topoisomerase in complex with DNA. A major outstanding question is the
way in which several inhibitors of topoisomerase I block the enzyme
action. We not only wish to understand the mode of action of known
topoisomerase inhibitors, but are also collaborating with synthetic
chemists to develop novel inhibitors on the basis of our crystal
structures, combined with molecular modeling and combinatorial chemistry

4. Structural studies on components of members of the very large
pyruvate dehydrogenase multi-enzyme complex family. These are wonderful,
multi-million Dalton complexes with a highly symmetric core surrounded
by a very dynamic and flexible arrangement of dozens of additional
proteins. We are focusing on components of these complexes from human,
Neisseria as well as other species.

 The positions require a great interest in medically oriented protein
crystallography and excellent crystallographic skills. Experience with
protein expression and purification methods is also required for most
projects. For some projects molecular biology know-how is beneficial,
for others experience in protein-DNA interactions and for yet others
knowledge of membrane protein crystallization would be a tremendous

 Please address applications including the full addresses, fax and
telephone numbers of three references to:

  Wim G.J. Hol
  Professor of Biological Structure and Biochemistry
  HHMI investigator
  Box 357742
  University of Washington
  Seattle WA 98195
  Fax: 206-685-7002
  Email: bmsc at

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