One of our principal research objectives is to derive a natural classification of the protein universe by unifying diverse protein superfamilies. However, the detection of relationships between these superfamilies is often non-trivial due to extensive divergence or variations, like circular permutations, in their structural scaffolds. This is particularly prevalent in numerous small folds involved in binding of nucleic-acids/nucleotides. One such alpha+beta fold that we recently identified was the RAGNYA fold that includes a diverse group of proteins principally involved in nucleic acid, nucleotide or peptide interactions. Members of the fold include the Ribosomal proteins L3 and L1, the GYF domain, DNA-recombination proteins of the NinB family from caudate bacteriophages, the C-terminal DNA-interacting domain of the Y-family DNA polymerases, the uncharacterized enzyme AMMECR1, the siRNA silencing repressor of tombusviruses, tRNA Wybutosine biosynthesis enzyme Tyw3p, DNA/RNA ligases and related nucleotidyltransferases and the Enhancer of rudimentary proteins. This fold exhibits three distinct circularly permuted versions and is composed of an internal repeat of a unit with two-strands and a helix. We show that despite considerable structural diversity in the fold, its representatives show a common mode of nucleic acid or nucleotide interaction via the exposed face of the sheet.
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