Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 19, Issue 8, Pages 782-787Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2329
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Funding
- Cancer Research UK
- Royal Society
- Wellcome Trust [090532/Z109/Z]
- Medical Research Council
- EP Abraham Research Fund
- BBSRC [BB/F013531/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F013531/1] Funding Source: researchfish
- Cancer Research UK [13070] Funding Source: researchfish
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Cytoplasmic terminal uridylyl transferases comprise a conserved family of enzymes that negatively regulate the stability or biological activity of a variety of eukaryotic RNAs, including mRNAs and tumor-suppressor let-7 microRNAs. Here we describe crystal structures of the Schizosaccharomyces pombe cytoplasmic terminal uridylyl transferase Cid1 in two apo conformers and bound to UTP. We demonstrate that a single histidine residue, conserved in mammalian Cid1 orthologs, is responsible for discrimination between VIP and ATP. We also describe a new high-affinity RNA substrate binding mechanism of Cid1, which is essential for enzymatic activity and is mediated by three basic patches across the surface of the enzyme. Overall, our structures provide a basis for understanding the activity of Cid1 and a mechanism of UTP selectivity conserved in its human orthologs, suggesting potential implications for anticancer drug design.
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