CNRS: A team at the
CNRS/ Inserm has evidenced, at the atomic scale, the threedimensional structure
of the complete human ribosome and the detailed interactions that occur within
it. These findings, obtained using a technology that is unique in France, open the
way to further exploring some of the adverse effects of antibiotics, and, in
the longer term, to the treatment of diseases related to ribosomal dysfunctions
and the deregulation of protein synthesis. This work is published in Nature on
22 April 2015.
Ribosomes are large complexes of
proteins and RNA folded together, which — within the cells of all living beings
— act as molecular nano-machines in the expression of genes and the
biosynthesis of proteins.
While the ribosomal structures of
different species were already known in detail at the atomic scale, determining
the particularly complex structure of the human ribosome remained a major
challenge.
The team led by Bruno Klaholz at
IGBMC (CNRS/Université de Strasbourg/Inserm) has now visualized the atomic
structure of the complete human ribosome at a resolution greater than 3
angströms (0.3 nanometers). The model obtained represents the 220,000 atoms
that make up the two subunits of the ribosome and makes it possible for the
first time to explore its detailed arrangement as well as visualize and
identify its different amino acids and nucleotides in 3D. The scientists
focused in particular on the various binding sites and detailed interactions
that occur within this structure. For example, their efforts revealed that
after delivering the amino acids they are carrying, transfer RNA continue to
interact with the ribosome at a specific site (the tRNA exit site). The team
has also shed light on the dynamics of the two ribosomal subunits, which
slightly rotate during the protein biosynthesis process, thus heavily remodelling
the 3D configuration of the structure at their interface.
These results were achieved using a
series of cutting-edge technologies. The samples were highly purified and then
frozen before being visualized through cryo-electron microscopy. This method
enables scientists to study fixed objects whose orientation does not change and
whose structure and biological functions are preserved. A combination of image
processing and 3D reconstruction applied to the images obtained by the
latest-generation cryo-electron microscope operated by the IGBMC1 — which is
unique in France
—made it possible to achieve this rare degree of accuracy. This detailed
knowledge of the structure and dynamics of the complete human ribosome opens
the way to further crucial explorations. It is now possible to envisage
studying the adverse effects of certain antibiotics designed to fight bacterial
ribosomes — and which may target the human ribosome "by mistake". Listing
existing binding sites is the first
step towards enhancing the specificity of therapeutic compounds and preventing
them from binding to the wrong site. In the longer term, these findings could
also help develop treatments for diseases linked to ribosomal dysfunctions and
the deregulation of protein synthesis. For example, in the case of cancers,
being able to target the ribosomes of diseased cells would make it possible to
reduce their protein synthesis rates.