Ribosome Decoding Methods Used by Humans and Bacteria Open Door to Novel Drug Discovery Opportunities

Scientists at St. Jude Children’s Research Hospital report that human ribosomes decode messenger RNA (mRNA) 10 times slower than bacterial ribosomes, but do so more accurately. The study “mRNA decoding in human is kinetically and structurally distinct from bacteria,” published in Nature, used a combination of structural biology approaches to better understand how ribosomes work.

The team pinpointed where the process slows down in humans, which will be useful information for developing new therapeutics for cancer and infections.

“In all species, ribosomes synthesize proteins by faithfully decoding messenger RNA (mRNA) nucleotide sequences using aminoacyl-tRNA substrates. Current knowledge of the decoding mechanism derives principally from studies on bacterial systems. Although key features are conserved across evolution, eukaryotes achieve higher-fidelity mRNA decoding than bacteria,” write the authors.

“In humans, changes in decoding fidelity are linked to ageing and disease and represent a potential point of therapeutic intervention in both viral and cancer treatment,” wrote the investigators. “Here we combine single-molecule imaging and cryogenic electron microscopy methods to examine the molecular basis of human ribosome fidelity to reveal that the decoding mechanism is both kinetically and structurally distinct from that of bacteria. Although decoding is globally analogous in both species, the reaction coordinate of aminoacyl-tRNA movement is altered on the human ribosome and the process is an order of magnitude slower.

“These distinctions arise from eukaryote-specific structural elements in the human ribosome and in the elongation factor eukaryotic elongation factor 1A (eEF1A) that together coordinate faithful tRNA incorporation at each mRNA codon. The distinct nature and timing of conformational changes within the ribosome and eEF1A rationalize how increased decoding fidelity is achieved and potentially regulated in eukaryotic species.”

By conducting mechanistic studies on bacterial and human ribosomes, researchers can understand their similarities and differences to develop drugs and understand disease. Many antibiotics work by targeting bacterial ribosomes. In humans, changes in how accurately ribosomes decode mRNA have been linked to aging and disease, representing a potential point of therapeutic intervention. The current study holds implications for the treatment of infections and cancer.

Targeting human ribosomes to find new therapeutics

“Bacteria have been well studied for many decades, but the kind of studies that we do, careful mechanistic studies, have been missing on human ribosomes,” said corresponding author, Scott Blanchard, PhD, St. Jude department of structural biology. “We’re interested in human ribosomes because those are what need to be targeted to find new treatments for cancer and viral infections.”

“We wanted to know how quickly a human ribosome can read the genetic code, how quickly it finds the tRNA that’s complementary to the mRNA,” explained said co-first author Mikael Holm, PhD. “We found that the process is about 10 times slower for human ribosomes than it is in bacteria. But this slow down adds accuracy, because human ribosomes are known to be more accurate at translating the code than bacterial ribosomes.”

Specifically, the researchers found that while humans and bacteria both decode mRNA, the reaction pathway of aminoacyl-tRNA movement during the decoding process is different on human ribosomes and is significantly slower. These differences arise from structural elements in the human ribosome and in the human elongation factor, eEF1A, that together are responsible for faithfully incorporating the right tRNA for each mRNA codon (piece of the sequence). The distinct nature and timing of conformational changes within the ribosome and eEF1A may explain how human ribosomes achieve greater decoding accuracy.

“With our cryo-EM structural studies, we were able to resolve human ribosome structures to atomic resolution, which revealed unprecedented features such as rRNA and protein modifications, ions and solvent molecules present in the human ribosome,” noted co-first author Kundhavai Natchiar, PhD. “These features finely characterize the molecular basis of interactions of the drug molecules with the human ribosome, which is indispensable for human ribosome–based drug design and discovery.”

To view additional studies on ribosomes, see GEN: “Getting to the Root of Aging through Ribosomes,” “Huntingtons Disease Found to Slow Down Ribosomes and Protein Synthesis,” and “Ribosomes Shown Translating mRNA from Maternally-inherited Mitochondrial Genome.”

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therapeutics
antibiotics