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Figure 2.12 A-minor interactions. Examples of hydrogen bonding patterns of consecutive A-minor interactions observed in 23S ribosomal RNA of H. marismortui 50S ribosome (a) and that between 23S and 5S ribosomal RNAs (b) (PDBID: 1FFK). Alphabets and numbers show nucleotide positions in the ribosomal RNAs. Hydrogen bonds are shown in dashed lines. Side view of three consecutive A-minor interactions is shown below.

      2.6.3.1 A-Minor Interactions

A-minor interactions are the most widely used in tertiary interaction of RNAs [24a]. These are characterized by insertion of minor groove edges of adenine nucleobases into minor groove of neighboring helices, preferentially where G·C base pairs are formed. Inserted adenine nucleobase forms hydrogen bonds with one or both of the 2′-hydroxyl group of the ribose in the base pair. There are various hydrogen bonding patterns in A-minor interactions (Figure 2.12). Formation of hydrogen bonds between bulged adenine and minor groove of the neighboring helix contributes to the stabilization of loop–helix and helix–helix interactions [25]. Although some of the A-minor interactions, which cause tight packing of the adenine nucleobase into the minor groove, could largely contribute to the thermodynamic stability of RNA tertiary structure [26], energetic contribution of each A-minor interaction is considered to be weaker than other tertiary interaction motifs with rigid structure characteristics. It is likely that the A-minor interaction plays roles assisting in the shaping of the tertiary structure of RNAs rather than stabilizing the structure.

      2.6.3.2 Ribose Zipper

Ribose zipper is also widely used interaction in RNA tertiary structures [24a]. It is usually characterized by two consecutive residues at one segment interact with two consecutive residues from another segment distant in the sequence through hydrogen bonding involving their 2′-hydroxy groups. Various classes of the ribose zipper interactions were proposed depending on the hydrogen bonding patterns [27]. In almost of the ribose zipper classes, two interacting RNA strands are in antiparallel orientation. The ribose zipper motif is often observed with other tertiary interactions such as A-minor interaction and GNRA tetraloop receptor interaction, which is described later (Section 2.6.3.5). For example, crystal structure of group I intron [28], one of the tertiary structures from which ribose zipper interactions were proposed, contains bulge–helix and loop–helix interactions involving the ribose zipper interaction (Figure 2.13). Both of which are associated with A-minor interaction or GAAA tetraloop receptor interaction. Since the contribution of the ribose zipper interaction on the stability of RNA tertiary structure is weaker than other tertiary interaction motifs [26, 29], as well as the A-minor interaction, ribose zipper interactions are considered to have roles supporting tertiary interactions. However, it is also considered that the ribose zipper interaction, which is provided by the 2′-hydroxy group unique for RNA ribose, is one of the indispensable factors to form complexed structures of RNAs.

Figure 2.13 Ribose zipper interactions in tertiary structure of group I intron derived from Tetrahymena thermophila (PDBID: 1GID). Overall tertiary structure (a) and enlarged images of different types of two ribose zipper interactions (b) are shown. Hydrogen bonds involved in the ribose zipper interactions are shown in dashed lines. Arrows show orientation of RNA strands.

      2.6.3.3 T-Loop Motif

T-loop motif is well-observed motif in the loop–loop interaction regions, which have been identified in a variety of RNAs [30]. T-loop motif generally consists of five consecutive nucleotides assuming a compact U-turn-like loop structure, in which the first and the fifth nucleobases form a base pair irrespective of whether it is canonical Watson–Crick or unusual one. When the T-loop motif is involved in the loop–loop interaction, the fourth and fifth nucleobases in the T-loop sandwich an extra nucleobase, which is derived from separated loop region, to make continuous base stacks. The sandwiched nucleobase usually interacts with the second nucleobase of the T-loop through hydrogen bonding [30]. In crystal structure of phenylalanyl-tRNA derived from Saccharomyces cerevisiae, in which T-loop motif was originally discovered, UUCGA loop of pentanucleotides accommodates guanine nucleobase from different tRNA loop region to form stable tertiary interaction (Figure 2.14).

      2.6.3.4 Kissing-Loop Interaction

Kissing-loop interaction is a basic type loop-loop interaction that causes cross-linkage between different helices, which are located in intrastrand or interstrand (Figure 2.15). The basic interaction of the kissing loop is formation of base pairing by complementary sequences in the apical loops of two hairpins. Intramolecular kissing complexes have been found in many RNA structures, ranging from transfer RNA (tRNA), in which length is shorter than 100 nucleotides, to ribosomal RNA (rRNA) with more than 1000 nucleotides [31]. The kissing-loop complex is usually stabilized by coaxial stacking of nucleobases included in the interhelical duplex (Figure 2.15) [32]. On the other hand, even if the sequence in the loop forms only two G·C base pairs without the coaxial stacking, a simplest kissing interaction is observed between hairpins each with a GACG tetraloop [33]. In that case, kissing base pairs are stabilized through cross-strand interactions caused by adjacent adenines in the loop [33].

Figure 2.14 T-loop motifs. (a) General secondary structure of T-loop motif consisting of neighboring stem loop and single-stranded regions. (b) Sequence and tertiary structures of yeast phenylalanine-tRNA containing T-loop motif (PDB ID: 1EHZ). Solid lines show sequence connectivity of different RNA regions involved in T-loop motif. Dashed lines show interaction between nucleobases. Enlarged image of T-loop motif surrounded by dashed circle at the overall structure is shown on right.

Figure 2.15 Kissing-loop interaction. (a) General secondary structure of kissing-loop interaction. (b) Sequence and tertiary structure

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