DNA polymerase template interactions probed by degenerate isosteric nucleobase analogs

Natasha Paul; Vishal C. Nashine; Geoffrey Hoops; Peiming Zhang; Jie Zhou; Donald E. Bergstrom; V. Jo Davisson

doi:10.1016/j.chembiol.2003.08.008

DNA polymerase template interactions probed by degenerate isosteric nucleobase analogs

Natasha Paul, Vishal C. Nashine, Geoffrey Hoops, Peiming Zhang, Jie Zhou, Donald E. Bergstrom, V. Jo Davisson

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

Abstract

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; Figure 1) 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.

Original language	English (US)
Pages (from-to)	815-825
Number of pages	11
Journal	Chemistry and Biology
Volume	10
Issue number	9
DOIs	https://doi.org/10.1016/j.chembiol.2003.08.008
State	Published - Sep 1 2003
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2003.08.008

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title = "DNA polymerase template interactions probed by degenerate isosteric nucleobase analogs",

abstract = "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; Figure 1) 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.",

author = "Natasha Paul and Nashine, {Vishal C.} and Geoffrey Hoops and Peiming Zhang and Jie Zhou and Bergstrom, {Donald E.} and Davisson, {V. Jo}",

note = "Funding Information: Financial support from the National Institutes of Health GM 53155 is gratefully acknowledged. We acknowledge the fellowship to V.C.N. from the Indiana Instrumentation Institute (III) supported by the Indiana 21 st Century Fund. Many helpful discussions with Alan Friedman are gratefully acknowledged. We are also grateful to Xiaoming Chen for technical assistance. ",

year = "2003",

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doi = "10.1016/j.chembiol.2003.08.008",

language = "English (US)",

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journal = "Chemistry and Biology",

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AU - Paul, Natasha

AU - Nashine, Vishal C.

AU - Hoops, Geoffrey

AU - Zhang, Peiming

AU - Zhou, Jie

AU - Bergstrom, Donald E.

AU - Davisson, V. Jo

N1 - Funding Information: Financial support from the National Institutes of Health GM 53155 is gratefully acknowledged. We acknowledge the fellowship to V.C.N. from the Indiana Instrumentation Institute (III) supported by the Indiana 21 st Century Fund. Many helpful discussions with Alan Friedman are gratefully acknowledged. We are also grateful to Xiaoming Chen for technical assistance.

PY - 2003/9/1

Y1 - 2003/9/1

N2 - 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; Figure 1) 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.

AB - 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; Figure 1) 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.

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JO - Chemistry and Biology

JF - Chemistry and Biology

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DNA polymerase template interactions probed by degenerate isosteric nucleobase analogs

Abstract

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