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.
• Kulshina, N., Baird, N.J., & Ferré-D'Amaré, A.R. Recognition of the bacterial second messenger cyclic diguanylate by its cognate riboswitch. Nature Struct. Mol. Biol. 16, 1212-1217 (2009). [abstract]
• Klein, D.J., Edwards, T.E. & Ferré-D'Amaré, A.R. Cocrystal structure of a class-I preQ1 riboswitch reveals a pseudoknot recognizing an essential hypermodified nucleobase. Nature Struct. Mol. Biol. 16, 343-344 (2009). [abstract]
• Xiao, H., Edwards, T.E. & Ferré-D'Amaré, A.R. Structural basis for specific, high-affinity tetracycline binding by an in vitro evolved aptamer and artificial riboswitch. Chem. Biol. 15, 1125-1137 (2008). [abstract]
• Klein, D.J., & Ferré-D’Amaré, A.R. Structural basis of glmS ribozyme activation by glucosamine-6-phosphate. Science 313, 1752-1756 (2006). [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]