9DA5

Crystal structure of human DNPH1 bound to inhibitor 2c

これはPDB形式変換不可エントリーです。

9DA5 の概要

• エントリーDOI: 10.2210/pdb9da5/pdb
• 関連するPDBエントリー: 4P5E 8QHQ
• 分子名称: 5-hydroxymethyl-dUMP N-hydrolase, [(3R,4R)-4-hydroxy-1-{[5-(hydroxymethyl)pyridin-3-yl]methyl}pyrrolidin-3-yl]methyl dihydrogen phosphate (3 entities in total)
• 機能のキーワード: inhibitor, complex, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 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: 33085.02

構造登録者

Wagner, A.G.,Schramm, V.L.,Almo, S.C.,Ghosh, A. (登録日: 2024-08-21, 公開日: 2025-02-05, 最終更新日: 2025-02-26)

主引用文献

Wagner, A.G.,Lang, T.B.D.,Ledingham, E.T.,Ghosh, A.,Brooks, D.,Eskandari, R.,Suthagar, K.,Almo, S.C.,Lamiable-Oulaidi, F.,Tyler, P.C.,Schramm, V.L.
Transition State Analogs of Human DNPH1 Reveal Two Electrophile Migration Mechanisms.
J.Med.Chem., 68:3653-3672, 2025

PubMed Abstract: DNPH1 is responsible for eliminating the epigenetically modified nucleotide, 5-hydroxymethyl-2'-deoxyuridine 5'-monophosphate (hmdUMP), preventing formation of hmdUTP, a mutation-inducing nucleotide. Loss of DNPH1 activity sensitizes PARP inhibition-resistant BRCA-deficient cancers by causing incorporation of hmdUTP into DNA. Hydrolysis of hmdUMP by DNPH1 proceeds through a covalent intermediate between Glu104 and 2-deoxyribose 5-phosphate, followed by hydrolysis, a reaction cycle with two transition states. We describe synthesis and characterization of transition state mimics for both transition states of DNPH1. Both transition states prefer inhibitors with cationic charge at the anomeric center and provide a foundation for inhibitor design. Ground-state complexes show reaction coordinate nucleophiles poised 3.3-3.7 Å from the anomeric carbon while transition state analogs tighten the reaction coordinate to place the nucleophiles 2.7-2.8 Å from the anomeric carbon. Crystal structures of DNPH1 with transition state analogs reveal transition states where the electrophilic ribocation migrates between the leaving groups and attacking nucleophiles.

PubMed: 39818772
DOI: 10.1021/acs.jmedchem.4c02778

実験手法

X-RAY DIFFRACTION (2.82 Å)