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Catalytic RNAs

Gene regulatory RNAs

RNA in signal transduction

RNA-protein interactions

RNA analogs of GFP

Small molecule recognition by RNA

RNA folding and dynamics

Molecular evolution

Methods

 

Ferré-D'Amaré Lab Research > Small molecule recognition by RNA

The ability of RNAs to interact specifically with small molecules underlies their function as ribozymes and riboswitches. We employ X-ray crystallography to determine the stereochemical principles of RNA-small molecule interactions, and a variety of biochemical and biophysical methods (such as calorimetry, various spectroscopies, light and X-ray scattering and hydrodynamics) to characterize their kinetics and thermodynamics. The majority of antibiotics in clinical use target the RNA component of the ribosome. Thus, RNA is a validated target for clinical intervention with small-molecule therapeutics. We employ a combination of synthetic chemistry, in vitro and in vivo screening and structural biology to discover new ligands to RNAs and to develop them into high-affinity, high specificity binders. These efforts to modulate RNA function with small molecules aim to lay the foundation for the discovery of antibiotic classes that function through previously untapped biological pathways.

• Baird, N.J., Inglese, J., & Ferré-D'Amaré, A.R. Rapid RNA-ligand interaction analysis through high-information content conformational and stability landscapes. Nature Comm. 6, 8898 (2015). [abstract]

• Warner, K.D., & Ferré-D'Amaré, A.R. Crystallographic analysis of TPP riboswitch binding by small-molecule ligands discovered through fragment-based drug discovery approaches. Meth. Enzymol. 549C, 221-233 (2014). [abstract]

• Warner, K.D., Homan, P., Weeks, K.M., Smith, A.G., Abell, C. & Ferré-D'Amaré, A.R. Validating fragment-based drug discovery for biological RNAs: lead fragments bind and remodel the TPP riboswitch specifically. Chem. Biol. 21, 591-595 (2014). [abstract]

• Deigan, K.E. & Ferré-D'Amaré, A.R. Riboswitches: discovery of drugs that target bacterial gene-regulatory RNAs. Acc. Chem. Res. 44, 1329-1338 (2011). [abstract]

• Edwards, T.E., & Ferré-D’Amaré, A.R. Crystal structures of the thi-box riboswitch bound to thiamine pyrophosphate analogs reveal adaptive RNA-small molecule recognition. Structure 14, 1459-1468 (2006). [abstract]