A PhD studentship (3 years) is available at the Institut de Biologie
Structurale (http://www.ibs.fr) in Grenoble, France. The project is to
explore the structural dynamics of the medically important enzyme
acetylcholinesterase by a panoply of complementary biophysical methods,
including kinetic crystallography.
During past decades, research in macromolecular biology focused mainly
on structure-function relationships. Yet, only by taking into account
the dynamic personality of macromolecules and by studying
structure-dynamics-function relationships can we understand biological
systems on the molecular level and in their cellular context.
Acetylcholinesterase, being one of Nature's fastest enzymes, represents
a major challenge concerning the study of its structural dynamics in the
context
of the enzyme's crucial role in cholinergic synapses. A particular focus
will be on changes in the structural dynamics of acetylcholinesterase
upon inhibitor binding. The results obtained will be exploited in a
collaborative effort to improve existing anti-Alzheimer drugs that
target acetylcholinesterase and to develop molecules capable of
reactivating poisoned acetylcholinesterase. Biophysical methods applied
include kinetic crystallography that films proteins in action, in
crystallo spectrophotometry, and molecular dynamics simulations. The
multidisciplinary project at the interface of biology, physics and
chemistry will be conducted in an international environment. It will
make extensive use of the nearby European Synchrotron Radiation Facility
(http://www.esrf.eu) and its Cryobench laboratory
(http://www.esrf.eu/UsersAndScience/Experiments/MX/Cryobench) dedicated
to in crystallo spectroscopic studies complementary to X-ray
crystallography.
Candidates should preferably have a biophysical education. Applications,
including two
letters of reference, should be sent to Dr. Martin Weik (w...@ibs.fr).
Representative publications
• Colletier, Fournier, Greenblatt, Stojan, Sussman, Zaccai, Silman &
Weik (2006) Structural insights into substrate traffic and
inhibition in acetylcholinesterase. EMBO J. 25, 2746.
• Colletier, Bourgeois, Sanson, Fournier, Sussman, Silman & Weik (2008)
Shoot-and-Trap: use of specific x-ray damage
to study structural protein dynamics by temperature-controlled
cryo-crystallography. PNAS 105, 11742.
• Xu, Colletier, Jiang, Silman, Sussman & Weik (2008) Induced-fit or
preexisting equilibrium dynamics? Lessons from protein crystallography
and MD simulations on acetylcholinesterase and implications for
structure-based drug design. Protein Sci., 17, 601.
• Weik & Colletier (2010) Temperature-dependent macromolecular X-ray
crystallography. Acta D 66, 437.
Press release related to the group's research on acetylcholienesterase
• Observing a target enzyme of Alzheimer’s disease drugs in action.
http://www.esrf.eu/news/spotlight/spotlight70/spotlight70/
• La cible de médicaments anti-Alzheimer observée en pleine action.
http://www2.cnrs.fr/presse/communique/1392.htm?debut=64
