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-Structure paper
タイトル | Structure of the human ATAD2 AAA+ histone chaperone reveals mechanism of regulation and inter-subunit communication. |
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ジャーナル・号・ページ | Commun Biol, Vol. 6, Issue 1, Page 993, Year 2023 |
掲載日 | 2023年9月28日 |
著者 | Carol Cho / Christian Ganser / Takayuki Uchihashi / Koichi Kato / Ji-Joon Song / |
PubMed 要旨 | ATAD2 is a non-canonical ATP-dependent histone chaperone and a major cancer target. Despite widespread efforts to design drugs targeting the ATAD2 bromodomain, little is known about the overall ...ATAD2 is a non-canonical ATP-dependent histone chaperone and a major cancer target. Despite widespread efforts to design drugs targeting the ATAD2 bromodomain, little is known about the overall structural organization and regulation of ATAD2. Here, we present the 3.1 Å cryo-EM structure of human ATAD2 in the ATP state, showing a shallow hexameric spiral that binds a peptide substrate at the central pore. The spiral conformation is locked by an N-terminal linker domain (LD) that wedges between the seam subunits, thus limiting ATP-dependent symmetry breaking of the AAA+ ring. In contrast, structures of the ATAD2-histone H3/H4 complex show the LD undocked from the seam, suggesting that H3/H4 binding unlocks the AAA+ spiral by allosterically releasing the LD. These findings, together with the discovery of an inter-subunit signaling mechanism, reveal a unique regulatory mechanism for ATAD2 and lay the foundation for developing new ATAD2 inhibitors. |
リンク | Commun Biol / PubMed:37770645 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.15 - 4.34 Å |
構造データ | EMDB-34468, PDB-8h3h: EMDB-36665, PDB-8juw: EMDB-36666, PDB-8juy: EMDB-36667, PDB-8juz: |
化合物 | ChemComp-ADP: ChemComp-ATP: |
由来 |
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キーワード | GENE REGULATION / Histone chaperone / AAA+ ATPase |