Abstract
In contrast to GNRA tetraloop receptors that are common in RNA, receptors for the more thermostable UNCG loops have remained elusive for almost three decades. An analysis of all RNA structures with resolution ≤3.0 Å from the PDB allowed us to identify three previously unnoticed receptors for UNCG and GNRA tetraloops that adopt a common UNCG fold, named 'Z-turn' in agreement with our previously published nomenclature. These receptors recognize the solvent accessible second Z-turn nucleotide in different but specific ways. Two receptors participating in a complex network of tertiary interactions are associated with the rRNA UUCG and GAAA Z-turns capping helices H62 and H35a in rRNA large subunits. Structural comparison of fully assembled ribosomes and comparative sequence analysis of >6500 rRNA sequences helped us recognize that these motifs are almost universally conserved in rRNA, where they may contribute to organize the large subunit around the subdomain-IV four-way junction. The third UCCG receptor was identified in a rRNA/protein construct crystallized at acidic pH. These three non-redundant Z-turn receptors are relevant for our understanding of the assembly of rRNA and other long-non-coding RNAs, as well as for the design of novel folding motifs for synthetic biology.