Volume 21, Issue 5, Pages (May 2014)

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Presentation transcript:

Volume 21, Issue 5, Pages 591-595 (May 2014) Validating Fragment-Based Drug Discovery for Biological RNAs: Lead Fragments Bind and Remodel the TPP Riboswitch Specifically Katherine Deigan Warner, Philip Homan, Kevin M. Weeks, Alison G. Smith, Chris Abell, Adrian R. Ferré-D’Amaré Chemistry & Biology Volume 21, Issue 5, Pages 591-595 (May 2014) DOI: 10.1016/j.chembiol.2014.03.007 Copyright © 2014 Elsevier Ltd Terms and Conditions

Chemistry & Biology 2014 21, 591-595DOI: (10. 1016/j. chembiol. 2014 Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 1 TPP- and Fragment-Bound Riboswitch Structures (A) 3D structure of the TPP riboswitch bound to TPP (Edwards and Ferré-D’Amaré, 2006) and secondary structure of the TPP riboswitch. (B) Interactions between the TPP riboswitch and bound cations with TPP. Metal ions and water molecules are in purple and red, respectively. (C) Interactions between the TPP riboswitch and bound cation with fragment 4. A portion of a composite, simulated annealing-omit 2|Fo| - |Fc| Fourier synthesis, contoured around the final refined fragment 4, G72, and the bound metal ion at 1.0 SD, is in cyan. See also Table S1 and Figures S1–S3 and S5. Chemistry & Biology 2014 21, 591-595DOI: (10.1016/j.chembiol.2014.03.007) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 2 SAXS Analysis of Fragment-Induced RNA Folding (A) SAXS analysis of the wild-type TPP riboswitch. P(r) plots reflect differences in shape and maximum dimension between the ligand-free, TPP-bound, and fragment 2-bound states of the riboswitch. SAXS behavior of the wild-type RNA, free or bound to TPP, is consistent with findings from a previous report (Baird and Ferré-D’Amaré, 2010). (B) SAXS analysis of the G72A TPP riboswitch. (C) SAXS analysis of the G72U TPP riboswitch. See also Table S2. Chemistry & Biology 2014 21, 591-595DOI: (10.1016/j.chembiol.2014.03.007) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 3 SHAPE Analysis of Fragment-Induced RNA Folding (A) SHAPE analyses of the ligand-free, fragment 2-bound and TPP-bound native sequence riboswitch. Black, yellow, and red in SHAPE profiles denote low, medium, and high reactivities, respectively. SHAPE data on the wild-type RNA, free or bound to TPP, are consistent with findings from a previous report (Steen et al., 2010). (B) SHAPE analyses of ligand-free, fragment 2-bound, and TPP-bound G72U mutant riboswitches. See also Figure S4. Chemistry & Biology 2014 21, 591-595DOI: (10.1016/j.chembiol.2014.03.007) Copyright © 2014 Elsevier Ltd Terms and Conditions