Scientists have cracked the structure
of an essential part of an enzyme believed to
play a key role in the development of many cancers.
The University of Colorado team
hopes its work will help explain how the enzyme,
telomerase, acts to make cancer cells "immortal".
The scientists also hope it could
lead to a new generation of more effective cancer
drugs.
Details are published in the
journal Nature Structural & Molecular Biology.
It is thought that over-activity
of telomerase contributes to the unchecked growth
of as many as 90% of human tumours.
The researchers say a lack of
detailed information about its structure has hindered
attempts to develop agents to block its effect.
Telomerase plays a key role in
the development of the human embryo during pregnancy,
by extending important areas at the tips of chromosomes
called telomeres.
In most healthy adult cells the
enzyme is completely shut down.
However, cancer cells find a
way to turn telomerase back on - triggering uncontrolled
cell division.
'Difficult to study'
It has previously proved difficult
to study telomerase in close detail because the
enzyme tends to clump together outside of cells,
preventing it from forming the ordered crystals
necessary for structural analysis.
The Colorado team solved the
problem by using a fluorescent green protein to
highlight rare fragments of the enzyme that did
not clump together in the usual way.
These came from a single-celled
organism called a tetrahymena - the same organism
in which telomerase was first discovered.
The researchers then used a few
more biochemical tricks to crystallise out the
protein fragments, and analyse them, eventually
producing an extremely detailed three-dimensional
atomic map.
They found that the protein fragment
had a deep groove on its surface.
It is thought that this might
be used to grab hold of the end of the chromosome
in order to extend its telomere region, and trigger
uncontrolled genetic division.
The researchers tested this theory
by making tiny structural changes to this grooved
area, and found this seemed to neutralise the
enzyme's action.
Lead researcher Dr Thomas Cech
said: "A molecule that would sit in that groove
looks like it would completely abolish the ability
of telomerase to work."
Dr Kat Arney, Science Information
Officer at Cancer Research UK, said: "Developing
therapies that block the action of telomerase
would be a great way to treat many types of cancer.
"Thanks to this research, we
now know more about the 3-D shape of the enzyme,
so scientists around the world can get to work
designing drugs to fit it precisely."
