6WZS

Fusibacterium ulcerans ZTP riboswitch bound to m-1-pyridinyl AICA

Summary for 6WZS

• Entry DOI: 10.2210/pdb6wzs/pdb
• Descriptor: Fusibacterium ulcerans ZTP riboswitch, POTASSIUM ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: riboswitch, pseudoknot, purine biosynthesis, aicar, rna
• Biological source: Fusobacterium ulcerans
• Total number of polymer chains: 2
• Total formula weight: 49152.10

Authors

Pichling, P.,Jones, C.P.,Ferre-D'Amare, A.R.,Tran, B. (deposition date: 2020-05-14, release date: 2021-03-24, Last modification date: 2023-10-18)

Primary citation

Tran, B.,Pichling, P.,Tenney, L.,Connelly, C.M.,Moon, M.H.,Ferre-D'Amare, A.R.,Schneekloth Jr., J.S.,Jones, C.P.
Parallel Discovery Strategies Provide a Basis for Riboswitch Ligand Design.
Cell Chem Biol, 27:1241-1249.e4, 2020

PubMed Abstract: Riboswitches are mRNA domains that make gene-regulatory decisions upon binding their cognate ligands. Bacterial riboswitches that specifically recognize 5-aminoimidazole-4-carboxamide riboside 5'-monophosphate (ZMP) and 5'-triphosphate (ZTP) regulate genes involved in folate and purine metabolism. Now, we have developed synthetic ligands targeting ZTP riboswitches by replacing the sugar-phosphate moiety of ZMP with various functional groups, including simple heterocycles. Despite losing hydrogen bonds from ZMP, these analogs bind ZTP riboswitches with similar affinities as the natural ligand, and activate transcription more strongly than ZMP in vitro. The most active ligand stimulates gene expression ∼3 times more than ZMP in a live Escherichia coli reporter. Co-crystal structures of the Fusobacterium ulcerans ZTP riboswitch bound to synthetic ligands suggest stacking of their pyridine moieties on a conserved RNA nucleobase primarily determines their higher activity. Altogether, these findings guide future design of improved riboswitch activators and yield insights into how RNA-targeted ligand discovery may proceed.

PubMed: 32795418
DOI: 10.1016/j.chembiol.2020.07.021

Experimental method

X-RAY DIFFRACTION (3.23 Å)