4QQ6

Crystal Structure of tudor domain of SMN1 in complex with a small organic molecule

4QQ6 の概要

• エントリーDOI: 10.2210/pdb4qq6/pdb
• 分子名称: Survival motor neuron protein, UNKNOWN ATOM OR ION, 4-methyl-2,3,4,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8(1H)-imine, ... (4 entities in total)
• 機能のキーワード: structural genomics, structural genomics consortium, sgc, rna binding protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q16637
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 7597.57

構造登録者

Liu, Y.,Tempel, W.,Iqbal, A.,Walker, J.R.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Brown, P.J.,Min, J.,Structural Genomics Consortium (SGC) (登録日: 2014-06-26, 公開日: 2014-08-06, 最終更新日: 2023-09-20)

主引用文献

Liu, Y.,Iqbal, A.,Li, W.,Ni, Z.,Wang, Y.,Ramprasad, J.,Abraham, K.J.,Zhang, M.,Zhao, D.Y.,Qin, S.,Loppnau, P.,Jiang, H.,Guo, X.,Brown, P.J.,Zhen, X.,Xu, G.,Mekhail, K.,Ji, X.,Bedford, M.T.,Greenblatt, J.F.,Min, J.
A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II.
Nat Commun, 13:5453-5453, 2022

PubMed Abstract: Survival of motor neuron (SMN) functions in diverse biological pathways via recognition of symmetric dimethylarginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to spinal muscular atrophy. Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that both the aromatic ring and imino groups of compound 1 contribute to its selective binding to SMN. Various on-target engagement assays support that compound 1 specifically recognizes SMN in a cellular context and prevents the interaction of SMN with the R1810me2s of RNA polymerase II subunit POLR2A, resulting in transcription termination and R-loop accumulation mimicking SMN depletion. Thus, in addition to the antisense, RNAi and CRISPR/Cas9 techniques, potent SMN antagonists could be used as an efficient tool to understand the biological functions of SMN.

PubMed: 36114190
DOI: 10.1038/s41467-022-33229-5

実験手法

X-RAY DIFFRACTION (1.75 Å)