2HXM

Complex of UNG2 and a small Molecule synthetic Inhibitor

2HXM の概要

• エントリーDOI: 10.2210/pdb2hxm/pdb
• 分子名称: Uracil-DNA glycosylase, 4-[(1E,7E)-8-(2,6-DIOXO-1,2,3,6-TETRAHYDROPYRIMIDIN-4-YL)-3,6-DIOXA-2,7-DIAZAOCTA-1,7-DIEN-1-YL]BENZOIC ACID (3 entities in total)
• 機能のキーワード: dna repair, uracil, uracil dna glycosylase, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform 1: Mitochondrion. Isoform 2: Nucleus: P13051
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25890.43

構造登録者

Bianchet, M.A.,Krosky, D.J.,Ghung, S.,Seiple, L.,Amzel, L.M.,Stivers, J.T. (登録日: 2006-08-03, 公開日: 2006-12-05, 最終更新日: 2023-08-30)

主引用文献

Krosky, D.J.,Bianchet, M.A.,Seiple, L.,Chung, S.,Amzel, L.M.,Stivers, J.T.
Mimicking damaged DNA with a small molecule inhibitor of human UNG2.
Nucleic Acids Res., 34:5872-5879, 2006

PubMed Abstract: Human nuclear uracil DNA glycosylase (UNG2) is a cellular DNA repair enzyme that is essential for a number of diverse biological phenomena ranging from antibody diversification to B-cell lymphomas and type-1 human immunodeficiency virus infectivity. During each of these processes, UNG2 recognizes uracilated DNA and excises the uracil base by flipping it into the enzyme active site. We have taken advantage of the extrahelical uracil recognition mechanism to build large small-molecule libraries in which uracil is tethered via flexible alkane linkers to a collection of secondary binding elements. This high-throughput synthesis and screening approach produced two novel uracil-tethered inhibitors of UNG2, the best of which was crystallized with the enzyme. Remarkably, this inhibitor mimics the crucial hydrogen bonding and electrostatic interactions previously observed in UNG2 complexes with damaged uracilated DNA. Thus, the environment of the binding site selects for library ligands that share these DNA features. This is a general approach to rapid discovery of inhibitors of enzymes that recognize extrahelical damaged bases.

PubMed: 17062624
DOI: 10.1093/nar/gkl747

実験手法

X-RAY DIFFRACTION (1.3 Å)