6TW3

HumRadA2 in complex with Naphthyl-HPA fragment-peptide chimera

6TW3 の概要

• エントリーDOI: 10.2210/pdb6tw3/pdb
• 分子名称: DNA repair and recombination protein RadA, PHOSPHATE ION, (2~{S})-1-[(2~{S})-2-[(3-azanylnaphthalen-2-yl)carbonylamino]-3-(1~{H}-imidazol-4-yl)propanoyl]-~{N}-[(2~{S})-1-azanyl-1-oxidanylidene-propan-2-yl]pyrrolidine-2-carboxamide, ... (4 entities in total)
• 機能のキーワード: rad51, recombinase, dna repair, dna binding protein
• 由来する生物種: Pyrococcus furiosus (strain ATCC 43587 / DSM 3638 / JCM 8422 / Vc1)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26183.63

構造登録者

Marsh, M.E.,Fischer, G.,Scott, D.E.,Coyne, A.G.,Skidmore, J.,Abell, C.,Hyvonen, M. (登録日: 2020-01-12, 公開日: 2021-01-27, 最終更新日: 2024-01-24)

主引用文献

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

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: 33662256
DOI: 10.1016/j.chembiol.2021.02.006

実験手法

X-RAY DIFFRACTION (1.352 Å)