7TRL

Crystal structure of human BIRC2 BIR3 domain in complex with histone H3

Summary for 7TRL

• Entry DOI: 10.2210/pdb7trl/pdb
• Descriptor: Baculoviral IAP repeat-containing protein 2, Histone H3, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: nuclear protein, inhibitor, histone h3, dna binding, apoptosis
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 12572.57

Authors

Klein, B.J.,Tencer, A.H.,Kutateladze, T.G. (deposition date: 2022-01-29, release date: 2023-08-02, Last modification date: 2023-09-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.74 Å)