RNA Structure and Function 261
Figure 7.10 The ribose-zipper motif in RNA packing. (a) The 2-OH group is bifunctional, serving as both H-bond
donor and acceptor. (b) and (c) Interdigitation of ribose residues in the core of the hepatitis delta
ribozyme
(Reprinted from Ref. 13. © (1998), with permission from Macmillan Publications Ltd)
cases, folding intermediates contribute to the formation of the native folded structure. In other cases, fold-
ing intermediates are inhibitory “kinetic traps,” or misfolded intermediates, that delay formation of the
native state.Misfoldingby RNA is considered to be a more serious problem than in proteins because RNA
secondary structural elements are often highly stable. As a result, many RNA molecules traverse a “rough
folding landscape,” in which misfolded states are prevalent, and in some cases as stable as the native state.
Thus when RNA is handled in vitro, it often needs to be refolded by careful denaturation and renaturation
procedures. In vivo, RNA chaperone proteins are likely to assist in proper RNA folding.^21
7.1.4.3 The Architecture of RNA Tertiary Structures. Once formed, RNA tertiary structures are
often stable, globular assemblies, which can be visualized by crystallography or through the creation of
molecular models that are based on biochemically obtained distance constraints. NMR has also been use-
ful in the elucidation of smaller RNA tertiary structures.
The first high-resolution crystal structure of a nucleic acid molecule was obtained for tRNA in 1972.22,23
Its secondary structure resembles a cloverleaf (Figure 7.6a), but in its folded form it is L-shaped (Figure
7.6b). The tRNA structure revealed several examples of non-Watson–Crick base pairs, base-triples, and
2 -OH tertiary interactions.
Twenty years later, substantial advances in RNA crystallography resulted in structure determination of
the hammerhead ribozyme^24 and a large stable subdomain (P456) within a group I intron RNA.^9 The P456
structuredemonstrated that a large RNA (160 nucleotides in this case) could be folded in vitro, crystal-
lized, and its structure solved by use of conventional methods (Figure 7.8). Since then, the crystal struc-
tures of many other large RNAs and ribozymes have been solved (Figures 7.9 and 7.20),13,25–27resulting in
a wealth of RNA tertiary-structure information. This success has been capped by high-resolution crystal