2HXM
Complex of UNG2 and a small Molecule synthetic Inhibitor
Summary for 2HXM
| Entry DOI | 10.2210/pdb2hxm/pdb |
| Descriptor | 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) |
| Functional Keywords | dna repair, uracil, uracil dna glycosylase, hydrolase |
| Biological source | Homo sapiens (human) |
| Cellular location | Isoform 1: Mitochondrion. Isoform 2: Nucleus: P13051 |
| Total number of polymer chains | 1 |
| Total formula weight | 25890.43 |
| Authors | Bianchet, M.A.,Krosky, D.J.,Ghung, S.,Seiple, L.,Amzel, L.M.,Stivers, J.T. (deposition date: 2006-08-03, release date: 2006-12-05, Last modification date: 2023-08-30) |
| Primary citation | 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 Cited by 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: 17062624DOI: 10.1093/nar/gkl747 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.3 Å) |
Structure validation
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