DNA polymerase template interactions probed by degenerate isosteric nucleobase analogs.
The development of novel artificial nucleobases and detailed X-ray crystal structures for primer/template/DNA polymerase complexes provide opportunities to assess DNA-protein interactions that dictate specificity. Recent results have shown that base pair shape recognition in the context of DNA polymerase must be considered a significant component. The isosteric azole carboxamide nucleobases (compounds 1-5; ) differ only in the number and placement of nitrogen atoms within a common shape and therefore present unique electronic distributions that are shown to dictate the selectivity of template-directed nucleotide incorporation by DNA polymerases. The results demonstrate how nucleoside triphosphate substrate selection by DNA polymerase is a complex phenomenon involving electrostatic interactions in addition to hydrogen bonding and shape recognition. These azole nucleobase analogs offer unique molecular tools for probing nonbonded interactions dictating substrate selection and fidelity of DNA polymerases.
Paul
Natasha
N
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Nashine
Vishal C
VC
Hoops
Geoffrey
G
Zhang
Peiming
P
Zhou
Jie
J
Bergstrom
Donald E
DE
Davisson
V Jo
VJ
D001393:Azoles / Q000737:chemistry; D020029:Base Pairing / Q000235:genetics; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D015335:Molecular Probes; D011687:Purines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D013237:Stereoisomerism; D013698:Templates, Genetic
D001393:Azoles; D015335:Molecular Probes; D011687:Purines; D011743:Pyrimidines; D004259:DNA-Directed DNA Polymerase