Science Concentrates STRUCTURAL BIOLOGY
A new view of the spliceosome Structural biologists capture important state of cellular machine that expands complexity of human genome Humans share a comparable number of protein-coding genes with the simple roundworm Caenorhabditis elegans, yet we are arguably more sophisticated organisms. This difference in complexity is thanks to the spliceosome, an enormous piece of biochemical machinery found in the nucleus. The spliceosome cuts out unnecessary sequences of freshly transcribed RNA called introns and joins the remaining sections to form messenger RNA. The variable way that the spliceosome combines the nonintron RNA results in about 10 times as many proteins in human cells as the number of genes in our genome. Now, thanks to cryo-electron microscopy, researchers have a new, near-atomic-level view of this cellular machine in its precatalytic state, before it has decided to start splicing RNA (Nature 2017, DOI: 10.1038/nature22799). Dozens of proteins and five protein-RNA complexes, called ribonucleoproteins, come and go as the spliceosome prunes
Two views of the spliceosome in its first precatalytic conformation. RNA after it has been transcribed from DNA and before protein production begins. The spliceosome undergoes seven colossal rearrangements during its assembly, activation, and catalysis. The current research—performed by Clemens Plaschka, Pei-Chun Lin, and Kiyoshi Nagai at the Medical Research Council Laboratory of
Molecular Biology—captured the spliceosome in the particularly important first arrangement when the machinery has loaded unspliced RNA but hasn’t yet gotten down to catalysis, comments Yigong Shi at Tsinghua University, who wasn’t involved in the work. This is a commitment step, an important decision-making point in splicing. The team found that 24 proteins associated with the spliceosome help keep the machine in a precatalytic state. Thereafter, these 24 proteins depart and another 22 arrive to help the spliceosome machinery undergo an extensive rearrangement in preparation for catalysis, Plaschka says. The work provides “a framework to dissect the activation mechanism and to determine the precise order of molecular events leading to formation of the spliceosome active site,” the researchers write. To date, four subsequent spliceosome states have been captured by structural biologists at near-atomic resolution, Shi adds. “This fifth structure is an important step closer to recapitulation of the entire catalytic splicing cycle.”—SARAH EVERTS
DRUG DISCOVERY
CREDIT: NAT U RE
When two drugs are better than one Drug combinations often have deleterious effects, but a new study reports a method to identify drugs that play nice with each other. Stefan Kubicek of the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and coworkers compiled a compound library to search for drugs that work better together than alone, and they used it to identify a combo that fights drug-resistant cancer (Nat. Chem. Biol. 2017, DOI: 10.1038/nchembio.2382). The list of more than 30,000 Food & Drug Administration-approved drug products is too large to screen efficiently for favorable combinations. Kubicek and co-
workers therefore narrowed down the list to a more easily screenable collection. They eliminated redundant drug products with identical active ingredients, removed biologicals, and made other selections to reduce the list to 954 systemically active small molecules. They grouped these compounds into classes based on their structures and known activities and then used software to help them select representative agents. The team used those agents and others to create a list of 308 compounds, which they call the CeMM Library of Unique Drugs, or CLOUD. Screening the CLOUD against cancer
cells revealed that the prostate cancer drug flutamide and the antithrombotic agent phenprocoumon work synergistically to kill an otherwise drug-resistant form of prostate cancer. Combinations of non-CLOUD drugs in the same classes as flutamide and phenprocoumon also fight the drug-resistant cancer, helping confirm that the CLOUD compounds successfully represent their classes and that the team’s reductionist concept is valid. “We believe that the CLOUD is the ideal set of compounds to develop all screening assays and to discover new applications for approved active ingredients,” Kubicek says.—STU BORMAN MAY 29, 2017 | CEN.ACS.ORG | C&EN
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