Validating fragment-based drug discovery for biological RNAs: lead fragments bind and remodel the TPP riboswitch specifically.

ABSTRACT: Thiamine pyrophosphate (TPP) riboswitches regulate essential genes in bacteria by changing conformation upon binding intracellular TPP. Previous studies using fragment-based approaches identified small molecule "fragments" that bind this gene-regulatory mRNA domain. Crystallographic studies now show that, despite having micromolar Kds, four different fragments bind the TPP riboswitch site-specifically, occupying the pocket that recognizes the aminopyrimidine of TPP. Unexpectedly, the unoccupied site that would recognize the pyrophosphate of TPP rearranges into a structure distinct from that of the cognate complex. This idiosyncratic fragment-induced conformation, also characterized by small-angle X-ray scattering and chemical probing, represents a possible mechanism for adventitious ligand

SUBMITTER: Warner KD 

PROVIDER: S-EPMC4057041 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature