3FCK: Complex of UNG2 and a fragment-based design inhibitor

Citation:
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.
PDB ID: 3FCKDownload
MMDB ID: 71394
PDB Deposition Date: 2008/11/21
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.64  Å
Source Organism:
Similar Structures:
Biological Unit for 3FCK: monomeric; determined by author and by software (PISA)
Molecular Components in 3FCK
Label Count Molecule
Protein (1 molecule)
1
Uracil-dna Glycosylase(Gene symbol: UNG)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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