Measurement of1H–1H Residual Dipolar Coupling Constants for Structural Studies of Medium Size Molecules

ChemPhysChem ◽  
2007 ◽  
Vol 8 (8) ◽  
pp. 1228-1235 ◽  
Author(s):  
Lan Jin ◽  
Tran N. Pham ◽  
Dušan Uhrín
Keyword(s):  
Dipolar Coupling ◽  
Residual Dipolar Coupling ◽  
Coupling Constants ◽  
Medium Size ◽  
Structural Studies

scholarly journals 2-amino-1,3-benzothiazole-6-carboxamide Preferentially Binds the Tandem Mismatch Motif r(UY:GA)

2020 ◽  
Author(s):  
Andrew T. Chang ◽  
Lu Chen ◽  
Luo Song ◽  
Shuxing Zhang ◽  
Edward P. Nikonowicz
Keyword(s):  
Small Molecules ◽  
Dipolar Coupling ◽  
Residual Dipolar Coupling ◽  
Three Dimensional ◽  
Coupling Constants ◽  
Dimensional Structure ◽  
Flanking Sequence ◽  
Base Pairs ◽  
Virtual Screen ◽  
Rna Hairpin

AbstractRNA helices are often punctuated with non-Watson-Crick features that can be the target of chemical compounds, but progress towards identifying small molecules specific for non-canonical elements has been slow. We have used a tandem UU:GA mismatch motif (5’-UG-3’:5’-AU-3’) embedded within the helix of an RNA hairpin as a model to identify compounds that bind the motif specifically. The three-dimensional structure of the RNA hairpin and its interaction with a small molecule compound identified through a virtual screen are presented. The G-A of the mismatch forms a sheared pair upon which the U-U base pair stacks. The hydrogen bond configuration of the U-U pair involves the O2 of the U adjacent to the G and the O4 of the U adjacent to the A. The G-A and U-U pairs are flanked by A-U and G-C base pairs, respectively, and the mismatch exhibits greater stability than when the motif is within the context of other flanking base pairs or when the 5’-3’ orientation of the G-A and U-U is swapped. Residual dipolar coupling constants were used to generate an ensemble of structures against which a virtual screen of 64,480 small molecules was performed to identify candidate compounds that the motif specifically binds. The tandem mismatch was found to be specific for one compound, 2-amino-1,3-benzothiazole-6-carboxamide, which binds with moderate affinity but extends the motif to include the flanking A-U and G-C base pairs. The finding that affinity for the UU:GA mismatch is flanking sequence dependent emphasizes the importance of motif context and potentially increases the number of small non-canonical features within RNA that can be specifically targeted by small molecules.

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