Identification of Spermidine Binding Site in T-box Riboswitch Antiterminator RNA

Chemical Biology & Drug Design
Jia LiuJ V Hines

Abstract

The T-box transcription antitermination riboswitch controls bacterial gene expression by structurally responding to uncharged, cognate tRNA. Previous studies indicated that cofactors, such as the polyamine spermidine, might serve a specific functional role in enhancing riboswitch efficacy. As riboswitch function depends on key RNA structural changes involving the antiterminator element, the interaction of spermidine with the T-box riboswitch antiterminator element was investigated. Spermidine binds antiterminator model RNA with high affinity (micromolar Kd ) based on isothermal titration calorimetry and fluorescence-monitored binding assays. NMR titration studies, molecular modeling, and inline and enzymatic probing studies indicate that spermidine binds at the 3' portion of the highly conserved seven-nucleotide bulge in the antiterminator. Together, these results support the conclusion that spermidine binds the T-box antiterminator RNA preferentially in a location important for antiterminator function. The implications of these findings are significant both for better understanding of the T-box riboswitch mechanism and for antiterminator-targeted drug discovery efforts.

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Citations

Dec 4, 2019·Infection and Immunity·Erin R MurphyPeter W Coschigano
Nov 20, 2019·Nature Structural & Molecular Biology·Shuang LiJinwei Zhang
Oct 18, 2020·Bioorganic & Medicinal Chemistry·Ian ArmstrongJennifer V Hines

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