Exploring GNRA tetraloop-like motifs in nucleic acid 3D structures

Structured nucleic acids play key roles in a variety of molecular mechanisms and have numerous applications in medicine and biotechnology. Stem-loops with specific tetraloop sequences, such as UNCG and GNRA, are among the most well-studied recurrent building blocks of structured RNAs, known to adopt very stable structures. The GNRA tetraloop motif frequently engages in long-range interactions with specific RNA receptors and can also be recognized by proteins. While several examples of GNRA-like conformations have been reported in non-tetraloop strands, no systematic survey has been conducted to explore the landscape of these variants. In this work, we report a comprehensive survey of GNRA tetraloop-like motifs within known 3D structures of nucleic acids, based solely on isostericity and without imposing restraints on sequence, loop type, backbone topology, or interactions involved. We identified twelve recurrent backbone topology variants of the motif, including all five possible two-strand variants and six three-strand variants. Among the pentaloop variants, we observed four different locations of the looped-out residues, with three of them directly interacting with proteins. These GNRA-like motifs highlight the versatility of favorable RNA 3D conformations to fit in diverse backbone contexts and modulate intermolecular interactions, which can be leveraged in RNA motif design.