X-ray lasers help fight sleeping sickness

WASHINGTON: Using the world's
most powerful X-ray free-electron
laser, an international team of
researchers has obtained new insight
into the structure of a medicinally
important protein that may serve as
a blueprint for the development of
drugs to fight sleeping sickness.
Sleeping sickness is caused by the
unicellular organism Trypanosoma
brucei that is transmitted by tsetse
flies. The disease kills about 30,000
people word-wide each year.
The currently available drugs against
the disease are of limited efficacy
and can have severe side effects.
Moreover, resistance against them is
increasing.
A promising drug target is the
protein Cathepsin B whose enzymatic
activity is vital for the parasite's
survival. Inhibitors of Cathepsin B
need to be highly specific against the
trypanosomal variant because it
resembles the human form.
The featured work by researchers,
including scientists of the Max Planck
Institute for Medical Research in
Heidelberg, provides detailed insight
into the structure of trypanosomal
Cathepsin B in a natively inhibited
form that might serve as a blueprint
for the rational design of drugs.
The biologically important form of
the protein was obtained by a trick:
instead of crystallizing the protein in
plastic trays in the lab, it was
crystallized in vivo in the cells that
produced the protein. This approach
provides natively modified proteins,
but the crystals obtained are tiny.
The use of the X-ray free-electron
laser (FEL) at Stanford was essential
for the work. Protein structures are
typically determined by exposing
crystals of the protein to X-rays.
Unfortunately, many of the most
interesting proteins, such a
membrane proteins, do not form
crystals of sufficient size for analysis
by conventional X-ray sources.
Measurements using very tiny
crystals have now become feasible
thanks to the extreme intensity of
FELs whose ultrashort pulse
durations outrun most radiation
damage effects. It is these properties
that allowed structure analysis of the
tiny in-vivo grown Cathepsin B
crystals.
Using a model system, the Heidelberg
researchers and their international
colleagues had previously validated
this new approach using FELs as a
tool for structure analysis, an
important step in the method
development that published in
February 2012 in Science.
The current featured research
demonstrates for the first time FEL
use to obtain new biologically
important information. The
international team shows in detail
how the structures of typanosomal
and human Cathepsin B differ and
how the naturally occurring native
inhibitor binds. This may provide
new ideas for designing drugs against
sleeping sickness.