Abstract
Quadruplex nucleic acids can be formed at the ends of eukaryotic chromosomes. Their formation and stabilisation by appropriate small molecules can be used as a means of inhibiting the telomere maintenance functions of telomerase in human cancer cells. The crystal structures have been determined for a number of complexes between these small molecules and human telomeric DNA and RNA quadruplexes. The detailed structural characteristics of these complexes have been surveyed here and the variations in conformation for the TTA and UUA loops have been explored. Loop conformations have been classified in terms of a number of discrete types and their distribution among the crystal structures. Sugar conformation and backbone angles have also been examined and trends highlighted. One particular loop class has been found to be most prevalent. Implications for in particular, rational drug design, are discussed.
Highlights
Quadruplex nucleic acids can be formed at the ends of eukaryotic chromosomes
The solution nuclear magnetic resonance (NMR) evidence for type-1 loops, which together with the diversity of crystal packing modes in the crystal structures, suggests that crystal packing forces are not contributing to the loop types
The preferred conformations of the relatively flexible loops are always among those most observed in these crystal structures
Summary
Atomic coordinates for the telomeric quadruplex structures were extracted from the Protein Data Bank (www.rcsb.org), with geometric and conformational analyses performed using the 3DNA program [92] at www.x3dna.org and visualised with the programs CHIMERA [93] at www.cgl.ucsf. edu/chimera and PyMOL [94] at www.pymol.org. If one considers the type-1 loop to represent the ‘native’ TTA loop conformation, the observation of a further 11 distinct loop conformations––many of which are dramatically different to the type-1 arrangement (see for example Figure 2b(ii))––indicates clearly that TTA propeller loops of human telomeric G-quadruplexes possess a significant degree of structural polymorphism This observation would be expected to have important consequences with respect to the rational design of small molecules targeted towards HTQs, the almost paradoxical observation of both type-1 and non-type-1 loops within a single ligandbound HTQ structure (e.g. PDB IDs 3CDM, 3CE5, 3SC8, 3UYH, 4DA3, 4DAQ) precludes a clear conclusion: small molecule compounds are able to elicit both dramatic and negligible effects on TTA loop geometry. This presumably reflects the energetic preference for C2’-endo puckered sugars in DNA, and suggests the less favourable C1’-exo and C3’-endo of the first two residues of the type-1 loops may be compensated for by the favourable energetics of base-base -stacking interactions
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