Cryo-EM catches the trypanosomatid trans-spliceosome at the moment it joins two RNAs

In a human cell, splicing cuts introns out of a transcript and joins what remains ^[15]. Trypanosomatids barely do that. "In these organisms, conventional intron splicing is extremely rare. Instead, virtually all of their messenger RNAs receive the same short RNA sequence, known as the SL RNA, at their 5' end. This step is essential for the maturation of their RNAs and therefore for the functioning of their cells," said Arnaud Vanden Broeck, who heads the Laboratory of RNA Structural Biology and Biochemistry at the University of Liege ^[8].

The selectivity argument for a drug rests on two facts about that step: the parasite cannot live without it, and it does not exist in this form in our cells ^[9]. Parts of it are familiar, though. "Despite some similarities with the splicing machinery found in our own cells, the trans-spliceosome has numerous distinctive adaptations," Vanden Broeck said ^[13]. A compound aimed at the conserved catalytic core would have the human spliceosome to contend with. The parasite-only proteins are where selectivity can be engineered, and the new structures place several of them ^[12].

Both structures come from cryogenic electron microscopy. "To obtain high-resolution snapshots of this machine in action, we used cryogenic electron microscopy (cryo-EM), a technique that involves freezing molecules very rapidly and then reconstructing their three-dimensional structure from hundreds of thousands of images," Vanden Broeck said ^[10]. The team captured the moment the SL RNA is attached to the messenger RNA, and the state immediately after the reaction is complete ^[11]. The paper is titled "Structural basis of step II spliced leader RNA trans-splicing in trypanosomatid parasites" ^[2], so the pair covers the second chemical step and its product.

What the work adds is coordinates. The functional case for targeting trans-splicing, essential and absent from human cells in this form, was available before anyone saw the machine ^[9]; the trans-spliceosome itself was discovered nearly 40 years ago, around 1986, and how its components were organised stayed unknown ^[3][4]. Vanden Broeck said the study "provides a concrete basis for designing molecules capable of specifically disrupting this machinery in parasites, while sparing human cells" ^[14]. The phys.org account reports no resolution in angstroms and no candidate molecule ^[16].

Scale, in the terms the source gives: leishmaniasis, sleeping sickness and Chagas disease affect several million people worldwide, and the drugs available are limited by efficacy, toxicity or the development of resistance ^[5][6]. Other trypanosomatids infect livestock, causing economic losses, and some infect crops and reduce yields ^[7]. All of them use the same trans-splicing step ^[18].

The structures also carry an evolutionary result, separate from the chemistry. The trans-spliceosome is an ancient machine, remodelled to do a different job ^[17].