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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 UTP 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.

Original publication

DOI

10.1038/nsmb.2329

Type

Journal article

Journal

Nat Struct Mol Biol

Publication Date

08/2012

Volume

19

Pages

782 - 787

Keywords

Amino Acid Sequence, Apoenzymes, Base Sequence, Catalytic Domain, Conserved Sequence, Crystallography, X-Ray, DNA Primers, Humans, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Nucleotidyltransferases, Protein Conformation, RNA, Fungal, Recombinant Proteins, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Sequence Homology, Amino Acid, Substrate Specificity, Uridine Triphosphate