9IDE

Human Deoxyhypusine Synthase Fragment Screening Campaign - ligand VT00096

これはPDB形式変換不可エントリーです。

9IDE の概要

• エントリーDOI: 10.2210/pdb9ide/pdb
• 分子名称: Deoxyhypusine synthase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, (4R)-2-METHYLPENTANE-2,4-DIOL, ... (6 entities in total)
• 機能のキーワード: fragment screening, polyamines, high-throughput, posttranslational modifications, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 83814.37

構造登録者

Wilk, P.,Wator-Wilk, E.,Krojer, T.,Grudnik, P. (登録日: 2025-02-15, 公開日: 2026-01-21, 最終更新日: 2026-01-28)

主引用文献

Wilk, P.,Wator-Wilk, E.,Muszak, D.,Kochanowski, P.,Krojer, T.,Grudnik, P.
Crystallographic fragment screening supports tool compound discovery and reveals conformational flexibility in human deoxyhypusine synthase.
Commun Chem, 2026

PubMed Abstract: Deoxyhypusine synthase (DHS) catalyzes the rate-limiting step of hypusination, a unique post-translational modification of eukaryotic translation factor 5 A (eIF5A). While DHS activity plays a critical role in both normal cellular processes and disease development, the lack of specific molecular tools has hindered detailed studies of this enzyme and the hypusination pathway in general. Existing inhibitors, such as polyamine analogs, suffer from limited specificity and versatility. In this study, we utilized crystallographic fragment screening (CFS) to identify potential DHS inhibitors and explore novel applications of this approach. With an unprecedented hit rate of 39%, we identified fragment clusters binding at key sites, including the active site entrance, the tetramer interface, the regulatory ball-and-chain motif, and potentially allosteric regions on the enzyme's surface. Notably, we discovered a covalent modifier that targets the catalytic lysine residue in an oxidoreductase reaction-specific manner, as well as fragments that induce significant structural rearrangements of crucial regulatory elements. Our findings establish a framework for extending CFS beyond traditional inhibitor discovery, demonstrating its utility in probing protein dynamics, identifying novel binding pockets, and investigating regulatory mechanisms. These results offer new insights into DHS function, hypusination dynamics, and the broader methodological advancements that CFS contributes to structural biology and protein regulation research.

PubMed: 41548022
DOI: 10.1038/s42004-026-01897-9

実験手法

X-RAY DIFFRACTION (1.47 Å)