Abstract:The potential of RNA molecules to be used as therapeutic targets by small inhibitors is now well established. In this fascinating wide-open field, aminoglycoside antibiotics constitute the most studied family of RNA binding drugs. Within the last three years, several x-ray crystal structures were solved for aminoglycosides complexed to one of their main natural targets in the bacterial cell, the decoding aminoacyl-tRNA site (A site). Other crystallographic structures have revealed the binding modes of aminogly… Show more
“…The neamine moiety of the gentamicin (and related aminoglycosides) is responsible for recognition of the target RNA A site (49). Gentamicin binds in the major groove of the A site, where the A ring stacks against G15 (equivalent to G1491 in the 30S ribosomal A site) and is anchored by a pseudo-base pair to A30 (A1408) (19).…”
“…The neamine moiety of the gentamicin (and related aminoglycosides) is responsible for recognition of the target RNA A site (49). Gentamicin binds in the major groove of the A site, where the A ring stacks against G15 (equivalent to G1491 in the 30S ribosomal A site) and is anchored by a pseudo-base pair to A30 (A1408) (19).…”
“…Structural transitions can also be used to inhibit the activity of RNA. For example, the antibiotic activity of aminoglycosides is largely derived from their ability to flip out two internal loop adenines in the ribosomal A-site (Fourmy et al 1996), which serves to disrupt decoding and the fidelity of translation (Vicens and Westhof 2003;Hermann 2006).…”
By simplifying the interpretation of nuclear magnetic resonance spin relaxation and residual dipolar couplings data, recent developments involving the elongation of RNA helices are providing new atomic insights into the dynamical properties that allow RNA structures to change functionally and adaptively. Domain elongation, in concert with spin relaxation measurements, has allowed the detailed characterization of a hierarchical network of local and collective motional modes occurring at nanosecond timescale that mirror the structural rearrangements that take place following adaptive recognition. The combination of domain elongation with residual dipolar coupling measurements has allowed the experimental threedimensional visualization of very large amplitude rigid-body helix motions in HIV-1 transactivation response element (TAR) that trace out a highly choreographed trajectory in which the helices twist and bend in a correlated manner. The dynamic trajectory allows unbound TAR to sample many of its ligand bound conformations, indicating that adaptive recognition occurs by ''conformational selection'' rather than ''induced fit.'' These studies suggest that intrinsic flexibility plays essential roles directing RNA conformational changes along specific pathways.
“…The physical presence of the water molecule W1 also widens the minor groove, in addition to forming a hydrogen bond to the N3 of A1493 to enable recognition. This type of U/U base pair, bridged by a water molecule, can be found in helix 44 of the ribosome in close proximity to the A1492-A1493 decoding center (Vicens and Westhof 2003). This U/U base pair with the bridging water is isosteric to canonical Watson-Crick base pairs and preserves the C19-C19 distance in a standard A-form helix.…”
Section: Rna Molecular Modeling Using Mc-symmentioning
A stop or nonsense codon is an in-frame triplet within a messenger RNA that signals the termination of translation. One common feature shared among all three nonsense codons (UAA, UAG, and UGA) is a uridine present at the first codon position. It has been recently shown that the conversion of this uridine into pseudouridine (C) suppresses translation termination, both in vitro and in vivo. Furthermore, decoding of the pseudouridylated nonsense codons is accompanied by the incorporation of two specific amino acids in a nonsense codon-dependent fashion. C differs from uridine by a single N 1 H group at the C5 position; how C suppresses termination and, more importantly, enables selective decoding is poorly understood. Here, we provide molecular rationales for how pseudouridylated stop codons are selectively decoded. Our analysis applies crystal structures of ribosomes in varying states of translation to consider weakened interaction of C with release factor; thermodynamic and geometric considerations of the codon-anticodon base pairs to rank and to eliminate mRNA-tRNA pairs; the mechanism of fidelity check of the codon-anticodon pairing by the ribosome to evaluate noncanonical codon-anticodon base pairs and the role of water. We also consider certain tRNA modifications that interfere with the C-coordinated water in the major groove of the codon-anticodon mini-helix. Our analysis of nonsense codons enables prediction of potential decoding properties for C-modified sense codons, such as decoding CUU potentially as Cys and Tyr. Our results provide molecular rationale for the remarkable dynamics of ribosome decoding and insights on possible reprogramming of the genetic code using mRNA modifications.
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