3FCI

Complex of UNG2 and a fragment-based designed inhibitor

Summary for 3FCI

• Entry DOI: 10.2210/pdb3fci/pdb
• Related: 3FCF 3FCK 3FCL
• Descriptor: Uracil-DNA glycosylase, 3-{(E)-[(3-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]amino}propoxy)imino]methyl}benzoic acid, SODIUM ION, ... (5 entities in total)
• Functional Keywords: dna repair, uracil, uracil dna glycosylase, alternative splicing, disease mutation, dna damage, glycosidase, host-virus interaction, hydrolase, mitochondrion, nucleus, phosphoprotein, transit peptide
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform 1: Mitochondrion. Isoform 2: Nucleus: P13051
• Total number of polymer chains: 1
• Total formula weight: 26029.63

Authors

Bianchet, M.A.,Chung, S.,Parker, J.B.,Amzel, L.M.,Stivers, J.T. (deposition date: 2008-11-21, release date: 2009-04-28, Last modification date: 2023-12-27)

Primary citation

Chung, S.,Parker, J.B.,Bianchet, M.,Amzel, L.M.,Stivers, J.T.
Impact of linker strain and flexibility in the design of a fragment-based inhibitor
Nat.Chem.Biol., 5:407-413, 2009

PubMed Abstract: The linking together of molecular fragments that bind to adjacent sites on an enzyme can lead to high-affinity inhibitors. Ideally, this strategy would use linkers that do not perturb the optimal binding geometries of the fragments and do not have excessive conformational flexibility that would increase the entropic penalty of binding. In reality, these aims are seldom realized owing to limitations in linker chemistry. Here we systematically explore the energetic and structural effects of rigid and flexible linkers on the binding of a fragment-based inhibitor of human uracil DNA glycosylase. Analysis of the free energies of binding in combination with cocrystal structures shows that the flexibility and strain of a given linker can have a substantial impact on binding affinity even when the binding fragments are optimally positioned. Such effects are not apparent from inspection of structures and underscore the importance of linker optimization in fragment-based drug discovery efforts.

PubMed: 19396178
DOI: 10.1038/nchembio.163

Experimental method

X-RAY DIFFRACTION (1.27 Å)