BIOINORGANIC CHEMISTRY A Short Course Second Edition

274 GROUP I AND II METALS IN BIOLOGICAL SYSTEMS: GROUP II

of the base forming the mutant causes structural deformation in the ribozyme;
(2) the perturbed structure may rearrange to make its site accessible to an
exogenous (added) base; and (3) binding of the rescuing base may restore the
active structure partially or completely and may even enhance catalysis. The
researchers found that the G 10.1 N 7 position is important in binding exogenous
guanine. Importantly, this is also the site of metal binding in X - ray structures.
The following factors for successful rescue were found to be important: (1) the
number of interactions formed with neighboring bases by the rescuing base;
(2) other local interactions (such as Me 2+ coordination at G 10.1 N 7 ); (3) base
stacking interactions [purines (A, G) stack better than pyrimidines (U, C)]; (4)
structural rigidity at the rescue site versus the ability to adopt alternative
structures; and (5) ability to align the RNA into a structural/functional mode
through formation of the base – sugar glycosidic bond. The researchers believe
that the rescued bases they studied were not necessarily involved in chemical
catalysis but rather in repair of conformational defects. They speculated that
the technique of base rescue could contribute to drug development and design
because RNA ribozymes are being pursued as therapeutic agents having the
potential to cleave deleterious RNAs.

Figure 6.14 Structure of 7 - deazaguanine (A), a reduced abasic nucleotide (B), and a
phenyl - substituted nucleotide (C).

HN

N NH

O

H 2 N

O H

H

H H

H H

O

OOP -

O

OOP -

5'

3'

reduced abasic nucleotide

O

H

H H

H H

O

OOP -

O

OOP -

5'

3'

phenyl nucleotide

B C

A

7-deazaguanine

7

8

1-deoxy-1-β-D-ribofuranose nucleotide 1-phenyl-1-β-D-ribofuranose nucleotide

base

substitution

here

base

substitution

here

N atom

removed here