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Crystal structure of an RNA duplex containing phenyl-ribonucleotides, hydrophobic isosteres of the natural pyrimidines

Published online by Cambridge University Press:  08 December 2000

GEORGE MINASOV
Affiliation:
Department of Molecular Pharmacology and Biological Chemistry and The Drug Discovery Program, Northwestern University Medical School, Chicago, Illinois 60611, USA
JASENKA MATULIC-ADAMIC
Affiliation:
Ribozyme Pharmaceuticals Inc., 2950 Wilderness Place, Boulder, Colorado 80301, USA
CHRISTOPHER J. WILDS
Affiliation:
Department of Molecular Pharmacology and Biological Chemistry and The Drug Discovery Program, Northwestern University Medical School, Chicago, Illinois 60611, USA New address: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235, USA.
PETER HAEBERLI
Affiliation:
Ribozyme Pharmaceuticals Inc., 2950 Wilderness Place, Boulder, Colorado 80301, USA
NASSIM USMAN
Affiliation:
Ribozyme Pharmaceuticals Inc., 2950 Wilderness Place, Boulder, Colorado 80301, USA
LEONID BEIGELMAN
Affiliation:
Ribozyme Pharmaceuticals Inc., 2950 Wilderness Place, Boulder, Colorado 80301, USA
MARTIN EGLI
Affiliation:
Department of Molecular Pharmacology and Biological Chemistry and The Drug Discovery Program, Northwestern University Medical School, Chicago, Illinois 60611, USA New address: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235, USA.
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Abstract

Chemically modified nucleotide analogs have gained widespread popularity for probing structure–function relationships. Among the modifications that were incorporated into RNAs for assessing the role of individual functional groups, the phenyl nucleotide has displayed surprising effects both in the contexts of the hammerhead ribozyme and pre-mRNA splicing. To examine the conformational properties of this hydrophobic base analog, we determined the crystal structure of an RNA double helix with incorporated phenyl ribonucleotides at 1.97 Å resolution. In the structure, phenyl residues are engaged in self-pairing and their arrangements suggest energetically favorable stacking interactions with 3′-adjacent guanines. The presence of the phenyl rings in the center of the duplex results in only moderate changes of the helical geometry. This finding is in line with those of earlier experiments that showed the phenyl analog to be a remarkably good mimetic of natural base function. Because the stacking interactions displayed by phenyl residues appear to be similar to those for natural bases, reduced conformational restriction due to the lack of hydrogen bonds with phenyl as well as alterations in its solvent structure may be the main causes of the activity changes with phenyl-modified RNAs.

Type
REPORT
Copyright
2000 RNA Society

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