7TRM

Crystal structure of human BIRC2 BIR3 domain in complex with inhibitor LCL-161

7TRM の概要

• エントリーDOI: 10.2210/pdb7trm/pdb
• 分子名称: Baculoviral IAP repeat-containing protein 2, ZINC ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: nuclear protein, inhibitor, histone h3, dna binding, apoptosis
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 11578.51

構造登録者

Tencer, A.H.,Klein, B.J.,Kutateladze, T.G. (登録日: 2022-01-29, 公開日: 2023-08-02, 最終更新日: 2023-09-20)

主引用文献

Tencer, A.H.,Yu, Y.,Causse, S.Z.,Campbell, G.R.,Klein, B.J.,Xuan, H.,Cartier, J.,Miles, M.A.,Gaurav, N.,Zadoroznyj, A.,Holt, T.A.,Wen, H.,Hawkins, C.J.,Spector, S.A.,Dubrez, L.,Shi, X.,Kutateladze, T.G.
Molecular basis for nuclear accumulation and targeting of the inhibitor of apoptosis BIRC2.
Nat.Struct.Mol.Biol., 30:1265-1274, 2023

PubMed Abstract: The inhibitor of apoptosis protein BIRC2 regulates fundamental cell death and survival signaling pathways. Here we show that BIRC2 accumulates in the nucleus via binding of its second and third BIR domains, BIRC2 and BIRC2, to the histone H3 tail and report the structure of the BIRC2-H3 complex. RNA-seq analysis reveals that the genes involved in interferon and defense response signaling and cell-cycle regulation are most affected by depletion of BIRC2. Overexpression of BIRC2 delays DNA damage repair and recovery of the cell-cycle progression. We describe the structural mechanism for targeting of BIRC2 by a potent but biochemically uncharacterized small molecule inhibitor LCL161 and demonstrate that LCL161 disrupts the association of endogenous BIRC2 with H3 and stimulates cell death in cancer cells. We further show that LCL161 mediates degradation of BIRC2 in human immunodeficiency virus type 1-infected human CD4 T cells. Our findings provide mechanistic insights into the nuclear accumulation of and blocking BIRC2.

PubMed: 37524969
DOI: 10.1038/s41594-023-01044-1

実験手法

X-RAY DIFFRACTION (2.4 Å)