4NYD

Crystal structure of the E. coli thiM riboswitch in complex with hypoxanthine

Summary for 4NYD

• Entry DOI: 10.2210/pdb4nyd/pdb
• Related: 4NYA 4NYB 4NYC 4NYG
• Descriptor: thiM TPP riboswitch, HYPOXANTHINE, MANGANESE (II) ION, ... (5 entities in total)
• Functional Keywords: fragment-based drug discovery, riboswitch, rna
• Biological source: Escherichia coli
• Total number of polymer chains: 1
• Total formula weight: 27362.59

Authors

Warner, K.D.,Homan, P.,Weeks, K.M.,Smith, A.G.,Abell, C.,Ferre-D'Amare, A.R. (deposition date: 2013-12-10, release date: 2014-06-04, Last modification date: 2023-09-20)

Primary citation

Warner, K.D.,Homan, P.,Weeks, K.M.,Smith, A.G.,Abell, C.,Ferre-D'Amare, 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

PubMed 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 discrimination by the riboswitch, and suggests that off-pathway conformations of RNAs can be targeted for drug development. Our structures, together with previous screening studies, demonstrate the feasibility of fragment-based drug discovery against RNA targets.

PubMed: 24768306
DOI: 10.1016/j.chembiol.2014.03.007

Experimental method

X-RAY DIFFRACTION (2.9 Å)