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| Hassan Belrhali [left] discusses with Amit Sharma [right] in the control cabin of the UK MRC-beamline BM14, at the ESRF |
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Press
Release 21 December 2005 [PDF]
Researchers at the International Centre for Genetic Engineering and
Biotechnology [ICGEB] in India and a unit of the
European Molecular Biology Laboratory [EMBL] in France
have made a key discovery about a molecule that helps
the malaria parasite infect human cells. India is one of the
countries most affected by this disease, which has
infected 300 million people across the world and leads to
over one million fatalities per year. The breakthrough,
which was achieved at the European Synchrotron
Radiation Facility [ESRF] in Grenoble, may represent an
important step towards finding new therapies. The study
appears in this week’s online edition of Nature [December
21].
Malaria is caused by a one-celled organism called
Plasmodium, which is passed to humans through the bite
of Anopheles mosquitoes. The parasite replicates inside
red blood cells, which eventually burst. In order to enter
these cells, it first has to bind to the cell through
interactions of proteins on the surfaces of red blood cells
and the parasite.
The new study reveals key features of a protein on the
surface of Plasmodium that permits it to bind. The
researchers obtained crystals of a module of this protein,
called the Duffy-Binding Like [DBL] domain, which directly
interacts with a "receptor" protein on red blood cells. Then
they examined the crystals using very powerful X-rays of
the UK-Medical Research Council Beamline BM14 at the
European Synchrotron Radiation Facility [ESRF] in
Grenoble. X-ray crystallography is one of the only
methods available to create atom-by-atom maps of
proteins, which are too small to be seen by microscopes.
"Until now we have not had a close-up view of the precise
surface where the two proteins interact," explains Amit
Sharma, the corresponding author of the paper. "That
surface is absolutely crucial in permitting the parasite to
enter the cell. If we can determine its features in atomic
detail, we may be able to find weak points that could make
good targets for drugs."
In addition to interfering with the binding process, such
drugs would also have to be specific: in other words, they
shouldn't interfere with normal processes in red blood
cells. The receptor protein that allows Plasmodium to
enter undoubtedly has other important functions. "What
we've found is that the DBL has an absolutely unique
architecture, which means that there should be a way to
inhibit its activity without affecting healthy blood cells,"
says Hassan Belrhali, an EMBL researcher who
participated in the project.
Evolution has produced many different species of
Plasmodium. This work was carried out using a form of the
parasite that doesn't normally infect humans, but DBL
modules are similar in different forms of the organism.
This makes it likely that the findings can be extended to
other types of Plasmodium. “Our results provide a
structural framework by which to understand the DBLs of
most malaria parasites, and could have an impact in the
design of drugs to fight against this illness,” explains Amit
Sharma.
The researchers are also investigating molecules
important at an earlier phase of malaria infections, when
parasites invade the liver.
Source article
S.K. Singh, R. Hora, H. Belrhali, C.E. Chitnis & A. Sharma. Structural basis for Duffy recognition by malaria parasite
Duffy-binding-like domain. Nature, online publication December 21, 2005.
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