6TV3
HumRadA1 in complex with 3-amino-2-naphthoic acid
Summary for 6TV3
| Entry DOI | 10.2210/pdb6tv3/pdb |
| Descriptor | DNA repair and recombination protein RadA, 3-azanylnaphthalene-2-carboxylic acid, PHOSPHATE ION, ... (5 entities in total) |
| Functional Keywords | rad51, recombinase, dna repair, dna binding protein |
| Biological source | Pyrococcus furiosus |
| Total number of polymer chains | 1 |
| Total formula weight | 25968.50 |
| Authors | Marsh, M.E.,Hyvonen, M. (deposition date: 2020-01-08, release date: 2021-01-27, Last modification date: 2024-01-24) |
| Primary citation | Scott, D.E.,Francis-Newton, N.J.,Marsh, M.E.,Coyne, A.G.,Fischer, G.,Moschetti, T.,Bayly, A.R.,Sharpe, T.D.,Haas, K.T.,Barber, L.,Valenzano, C.R.,Srinivasan, R.,Huggins, D.J.,Lee, M.,Emery, A.,Hardwick, B.,Ehebauer, M.,Dagostin, C.,Esposito, A.,Pellegrini, L.,Perrior, T.,McKenzie, G.,Blundell, T.L.,Hyvonen, M.,Skidmore, J.,Venkitaraman, A.R.,Abell, C. A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death. Cell Chem Biol, 28:835-, 2021 Cited by PubMed Abstract: 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 K of 366 nM. The quinoline of CAM833 occupies a hotspot, the Phe-binding pocket on RAD51 and the methyl of the substituted α-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. PubMed: 33662256DOI: 10.1016/j.chembiol.2021.02.006 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
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