6tw3

HumRadA2 in complex with Naphthyl-HPA fragment-peptide chimera

spinqualitylabelsall models 6tw3, resolution 1.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6tw3 is a 1 chain structure with sequence from Pyrococcus furiosus DSM 3638. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.352Å Ligands: O0E, PO4 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 BRCA2 controls RAD51 recombinase during homologous DNA recombination (HDR) through eight evolutionarily conserved BRC repeats, which individually engage RAD51 via the motif Phe-x-x-Ala. Using structure-guided molecular design, templated on a monomeric thermostable chimera between human RAD51 and archaeal RadA, we identify CAM833, a 529 Da orthosteric inhibitor of RAD51:BRC with a Kd of 366 nM. The quinoline of CAM833 occupies a hotspot, the Phe-binding pocket on RAD51 and the methyl of the substituted alpha-methylbenzyl group occupies the Ala-binding pocket. In cells, CAM833 diminishes formation of damage-induced RAD51 nuclear foci; inhibits RAD51 molecular clustering, suppressing extended RAD51 filament assembly; potentiates cytotoxicity by ionizing radiation, augmenting 4N cell-cycle arrest and apoptotic cell death and works with poly-ADP ribose polymerase (PARP)1 inhibitors to suppress growth in BRCA2-wildtype cells. Thus, chemical inhibition of the protein-protein interaction between BRCA2 and RAD51 disrupts HDR and potentiates DNA damage-induced cell death, with implications for cancer therapy. A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death.,Scott DE, Francis-Newton NJ, Marsh ME, Coyne AG, Fischer G, Moschetti T, Bayly AR, Sharpe TD, Haas KT, Barber L, Valenzano CR, Srinivasan R, Huggins DJ, Lee M, Emery A, Hardwick B, Ehebauer M, Dagostin C, Esposito A, Pellegrini L, Perrior T, McKenzie G, Blundell TL, Hyvonen M, Skidmore J, Venkitaraman AR, Abell C Cell Chem Biol. 2021 Mar 1. pii: S2451-9456(21)00058-1. doi:, 10.1016/j.chembiol.2021.02.006. PMID:33662256 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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