7SEC

Crystal structure of human Fibrillarin in complex with compound 1a

7SEC の概要

• エントリーDOI: 10.2210/pdb7sec/pdb
• 分子名称: rRNA 2'-O-methyltransferase fibrillarin, FORMIC ACID, 2-[(8S)-4-oxo-2-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]pyrazin-6-yl]acetamide, ... (5 entities in total)
• 機能のキーワード: methyltransferase, s-adenosyl methionine, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 54407.99

構造登録者

Shi, Y.,El-Deeb, I.M.,Masic, V.,Hartley-Tassell, L.,Maggioni, A.,von Itzstein, M.,Ve, T. (登録日: 2021-09-30, 公開日: 2022-02-09, 最終更新日: 2023-10-18)

主引用文献

Shi, Y.,El-Deeb, I.M.,Masic, V.,Hartley-Tassell, L.,Maggioni, A.,Itzstein, M.V.,Ve, T.
Discovery of Cofactor Competitive Inhibitors against the Human Methyltransferase Fibrillarin.
Pharmaceuticals, 15:-, 2021

PubMed Abstract: Fibrillarin (FBL) is an essential and evolutionarily highly conserved S-adenosyl methionine (SAM) dependent methyltransferase. It is the catalytic component of a multiprotein complex that facilitates 2'--methylation of ribosomal RNAs (rRNAs), a modification essential for accurate and efficient protein synthesis in eukaryotic cells. It was recently established that human FBL (hFBL) is critical for Nipah, Hendra, and respiratory syncytial virus infections. In addition, overexpression of hFBL contributes towards tumorgenesis and is associated with poor survival in patients with breast cancer, suggesting that hFBL is a potential target for the development of both antiviral and anticancer drugs. An attractive strategy to target cofactor-dependent enzymes is the selective inhibition of cofactor binding, which has been successful for the development of inhibitors against several protein methyltransferases including PRMT5, DOT1L, and EZH2. In this work, we solved crystal structures of the methyltransferase domain of hFBL in apo form and in complex with the cofactor SAM. Screening of a fluorinated fragment library, via X-ray crystallography and 19F NMR spectroscopy, yielded seven hit compounds that competed with cofactor binding, two of which resulted in co-crystal structures. One of these structures revealed unexpected conformational variability in the cofactor binding site, which allows it to accommodate a compound significantly different from SAM. Our structural data provide critical information for the design of selective cofactor competitive inhibitors targeting hFBL, and preliminary elaboration of hit compounds has led to additional cofactor site binders.

PubMed: 35056083
DOI: 10.3390/ph15010026

実験手法

X-RAY DIFFRACTION (1.9 Å)