8GLA

Co-crystal structure of caPCNA bound to the AOH1996 derivative, AOH1996-1LE

8GLA の概要

• エントリーDOI: 10.2210/pdb8gla/pdb
• 分子名称: Proliferating cell nuclear antigen, N-[2-(3-methoxyphenoxy)phenyl]-N~2~-(naphthalene-1-carbonyl)-L-alpha-glutamine, CHLORIDE ION (3 entities in total)
• 機能のキーワード: pcna, transcription-replication conflict, dna replication stress, dna repair, aoh1160, aoh1996, dna binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 118457.79

構造登録者

Jossart, J.,Perry, J.J. (登録日: 2023-03-21, 公開日: 2023-07-26, 最終更新日: 2024-10-16)

主引用文献

Gu, L.,Li, M.,Li, C.M.,Haratipour, P.,Lingeman, R.,Jossart, J.,Gutova, M.,Flores, L.,Hyde, C.,Kenjic, N.,Li, H.,Chung, V.,Li, H.,Lomenick, B.,Von Hoff, D.D.,Synold, T.W.,Aboody, K.S.,Liu, Y.,Horne, D.,Hickey, R.J.,Perry, J.J.P.,Malkas, L.H.
Small molecule targeting of transcription-replication conflict for selective chemotherapy.
Cell Chem Biol, 30:1235-, 2023

PubMed Abstract: Targeting transcription replication conflicts, a major source of endogenous DNA double-stranded breaks and genomic instability could have important anticancer therapeutic implications. Proliferating cell nuclear antigen (PCNA) is critical to DNA replication and repair processes. Through a rational drug design approach, we identified a small molecule PCNA inhibitor, AOH1996, which selectively kills cancer cells. AOH1996 enhances the interaction between PCNA and the largest subunit of RNA polymerase II, RPB1, and dissociates PCNA from actively transcribed chromatin regions, while inducing DNA double-stranded breaks in a transcription-dependent manner. Attenuation of RPB1 interaction with PCNA, by a point mutation in RPB1's PCNA-binding region, confers resistance to AOH1996. Orally administrable and metabolically stable, AOH1996 suppresses tumor growth as a monotherapy or as a combination treatment but causes no discernable side effects. Inhibitors of transcription replication conflict resolution may provide a new and unique therapeutic avenue for exploiting this cancer-selective vulnerability.

PubMed: 37531956
DOI: 10.1016/j.chembiol.2023.07.001

実験手法

X-RAY DIFFRACTION (3.77 Å)