8VQV

Structure of S. odontolytica ZTP riboswitch bound to m-1-pyridinyl-AICA

Summary for 8VQV

• Entry DOI: 10.2210/pdb8vqv/pdb
• Descriptor: RNA (64-MER), MAGNESIUM ION, 5-amino-1-(pyridin-3-yl)-1H-imidazole-4-carboxamide, ... (4 entities in total)
• Functional Keywords: riboswitch, drug, synthetic, aptamer, rna
• Biological source: Schaalia odontolytica
• Total number of polymer chains: 1
• Total formula weight: 21034.26

Authors

Jones, C.P.,Ferre D'Amare, A.R. (deposition date: 2024-01-19, release date: 2025-06-11, Last modification date: 2025-08-06)

Primary citation

Fullenkamp, C.R.,Mehdi, S.,Jones, C.P.,Tenney, L.,Pichling, P.,Prestwood, P.R.,Ferre-D'Amare, A.R.,Tiwary, P.,Schneekloth, J.S.
Machine Learning-Augmented Molecular Dynamics Simulations (MD) Reveal Insights Into the Disconnect Between Affinity and Activation of ZTP Riboswitch Ligands.
Angew.Chem.Int.Ed.Engl., 64:e202505971-e202505971, 2025

PubMed Abstract: The challenge of targeting RNA with small molecules necessitates a better understanding of RNA-ligand interaction mechanisms. However, the dynamic nature of nucleic acids, their ligand-induced stabilization, and how conformational changes influence gene expression pose significant difficulties for experimental investigation. This work employs a combination of computational and experimental methods to address these challenges. By integrating structure-informed design, crystallography, and machine learning-augmented all-atom molecular dynamics simulations (MD), we synthesized, biophysically and biochemically characterized, and studied the dissociation of a library of small molecule activators of the 5-aminoimidazole-4-carboxamide ribonucleotide triphosphate (ZTP) riboswitch, a ligand-binding RNA motif that regulates bacterial gene expression. We uncovered key interaction mechanisms, revealing valuable insights into the role of ligand binding kinetics on riboswitch activation. Further, we established that ligand on-rates determine activation potency as opposed to binding affinity and elucidated RNA structural differences, which provide mechanistic insights into the interplay of RNA structure on riboswitch activation.

PubMed: 40310613
DOI: 10.1002/anie.202505971

Experimental method

X-RAY DIFFRACTION (2.43 Å)