4b35 | pdb_00004b35

Humanised monomeric RadA in complex with 4-methylester indole

spinqualitylabelsall models 4b35, resolution 1.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4b35 is a 1 chain structure with sequence from Atcc 43587. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 4ME, PO4 Related: 1pzn, 4a6p, 4a6x, 4a74, 4a7o, 4b2i, 4b2l, 4b2p, 4b32, 4b33, 4b34 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [RADA_PYRFU] Involved in DNA repair and in homologous recombination. Binds and assemble on single-stranded DNA to form a nucleoprotein filament. Hydrolyzes ATP in a ssDNA-dependent manner and promotes DNA strand exchange between homologous DNA molecules. Publication Abstract from PubMed The ability to identify inhibitors of protein-protein interactions represents a major challenge in modern drug discovery and in the development of tools for chemical biology. In recent years, fragment-based approaches have emerged as a new methodology in drug discovery; however, few examples of small molecules that are active against chemotherapeutic targets have been published. Herein, we describe the fragment-based approach of targeting the interaction between the tumour suppressor BRCA2 and the recombination enzyme RAD51; it makes use of a screening pipeline of biophysical techniques that we expect to be more generally applicable to similar targets. Disruption of this interaction in vivo is hypothesised to give rise to cellular hypersensitivity to radiation and genotoxic drugs. We have used protein engineering to create a monomeric form of RAD51 by humanising a thermostable archaeal orthologue, RadA, and used this protein for fragment screening. The initial fragment hits were thoroughly validated biophysically by isothermal titration calorimetry (ITC) and NMR techniques and observed by X-ray crystallography to bind in a shallow surface pocket that is occupied in the native complex by the side chain of a phenylalanine from the conserved FxxA interaction motif found in BRCA2. This represents the first report of fragments or any small molecule binding at this protein-protein interaction site. Using a Fragment-Based Approach To Target Protein-Protein Interactions.,Scott DE, Ehebauer MT, Pukala T, Marsh M, Blundell TL, Venkitaraman AR, Abell C, Hyvonen M Chembiochem. 2013 Jan 23. doi: 10.1002/cbic.201200521. PMID:23344974 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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