7TZR

Crystal structure of the E. coli thiM riboswitch bound to N-methyl-1-(quinoxalin-6-yl)methanamine (compound 16)

7TZR の概要

• エントリーDOI: 10.2210/pdb7tzr/pdb
• 分子名称: RNA (80-MER), N-methyl-1-(quinoxalin-6-yl)methanamine, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: thim tpp riboswitch, rna
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 52517.32

構造登録者

Nuthanakanti, A.,Serganov, A. (登録日: 2022-02-16, 公開日: 2022-05-25, 最終更新日: 2023-10-18)

主引用文献

Zeller, M.J.,Favorov, O.,Li, K.,Nuthanakanti, A.,Hussein, D.,Michaud, A.,Lafontaine, D.A.,Busan, S.,Serganov, A.,Aube, J.,Weeks, K.M.
SHAPE-enabled fragment-based ligand discovery for RNA.
Proc.Natl.Acad.Sci.USA, 119:e2122660119-e2122660119, 2022

PubMed Abstract: The transcriptome represents an attractive but underused set of targets for small-molecule ligands. Here, we devise a technology that leverages fragment-based screening and SHAPE-MaP RNA structure probing to discover small-molecule fragments that bind an RNA structure of interest. We identified fragments and cooperatively binding fragment pairs that bind to the thiamine pyrophosphate (TPP) riboswitch with millimolar to micromolar affinities. We then used structure-activity relationship information to efficiently design a linked-fragment ligand, with no resemblance to the native ligand, with high ligand efficiency and druglikeness, that binds to the TPP thiM riboswitch with high nanomolar affinity and that modulates RNA conformation during cotranscriptional folding. Principles from this work are broadly applicable, leveraging cooperativity and multisite binding, for developing high-quality ligands for diverse RNA targets.

PubMed: 35561226
DOI: 10.1073/pnas.2122660119

実験手法

X-RAY DIFFRACTION (2.7 Å)