MAKING SURE ANTIBIOTICS AS THEY SHOULD
Researchers at ETH
Zurich are decoding the structure of the large ribosomal subunit of the
mitochondria at an atomic level, thereby providing insight into the molecular
architecture of this ribosome with implications for a better understanding of
the mode of action of antibiotics.
A
team of ETH Zurich researchers led by professors Nenad Ban and Ruedi Aebersold
have studied the highly complex molecular structure of mitoribosomes, which are
the ribosomes of mitochondria. Ribosomes are found in the cells of all living
organisms. However, higher organisms (eukaryotes), which include fungi, plants,
animals and humans, contain much more complex ribosomes than bacteria. In
eukaryotes, ribosomes can also be divided into two types: those in the cytosol
-- which comprises the majority of the cell -- and those found in the
mitochondria or "power plants" of cells. Mitochondria are only found
in eukaryotes.
Ribosomes
serve as translation devices for the genetic code and produce proteins based on
the information stored in DNA. Every ribosome consists of two subunits. The
smaller subunit uses transfer ribonucleic acids (transfer RNA or tRNA) to
decode the genetic code it receives in the form of messenger RNA, while the
larger subunit joins the amino acids delivered by the transfer RNA together
like a string of pearls.
Even
higher resolution, even more details
Mitochondrial
ribosomes are especially difficult to study because they are found only in
small amounts and are difficult to isolate. At the beginning of the year, ETH
researchers had shed light on the molecular structure of the large subunit of
the mitoribosome in mammalian cells to a resolution of 4.9 Ã… (less than 0.5
nm). However, this resolution was not adequate to reliably build a complete atomic
model of this previously unknown structure. The team lead by ETH Professor
Nenad Ban has now succeeded in this task and was able to map the entire
structure at a resolution of 3.4 Ã… (0.34 nm). The researchers recently
published their findings in the scientific journal Nature.
The
scientists used high-resolution cryo-electron microscopy at the Electron
Microscopy Center of ETH Zurich (ScopeM) and state-of-the-art mass spectrometry
methods in their experiments. Thanks to recent technical advances in cryo-electron
microscopy and the development of direct electron detection cameras that can
correct for specimen motion during the exposure, it only recently became
possible to capture images of biomolecules at a resolution of less than four
angstroms.
Improving
the effect of antibiotics
In
particular, the new images show the details of the peptidyl transferase centre
(PTC), which is where the amino acid building blocks are combined. The proteins
synthesised in this way then pass through a tunnel, where they finally exit the
large subunit of the ribosome.
"This
process is medically relevant," said Basil Greber, lead author of the
study and postdoctoral researcher in Nenad Ban's group. The reason is that this
tunnel is a target for certain antibiotics. The antibiotic becomes lodged in
the tunnel and prevents the proteins that have just been synthesized from
leaving the tunnel. However, antibiotics should only inhibit protein synthesis
in the ribosomes of bacteria.
"For
an antibiotic to be used in humans, it must not attack human ribosomes," explains
Greber. Antibiotics must inhibit protein synthesis only in bacterial ribosomes.
The problem is that mitochondrial ribosomes resemble those of bacteria, which
is why certain antibiotics also interfere with mitoribosomes. "This can
lead to serious side effects." The ETH researchers' findings will make it
possible in the future to design antibiotics that inhibit only bacterial and
not mitochondrial ribosomes. This is one basic requirement for using them in
clinical applications.
A
surprising discovery
The
ETH researchers also made an unexpected discovery. They found that
mitoribosomes use transfer RNA in two fundamentally different ways. Firstly,
the tRNA is used to select the right amino acid for peptide synthesis in the
PTC. Secondly, one tRNA is a fixed part of the structure, unlike in all other
ribosomes. Although it has been known for quite some time that mitochondrial
ribosomes integrated new proteins into their structure over the course of their
development, this is the first time that the use of an entirely new RNA
molecule was observed. "This demonstrates the great evolutionary
plasticity of mitoribosomes," underscored Greber.
The
ETH team is now faced with a major, still unresolved task in its research:
determining the structure of the smaller subunit of the mitochondrial ribosome.
The fact that it is more flexible than the large subunit renders this
undertaking an even greater challenge.
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