+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 7ccr | ||||||||||||||||||||||||
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タイトル | Structure of the 2:2 cGAS-nucleosome complex | ||||||||||||||||||||||||
要素 |
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キーワード | STRUCTURAL PROTEIN/TRANSFERASE/DNA / cGAS / nucleosome / inhibition / cryo-EM / IMMUNE SYSTEM / STRUCTURAL PROTEIN-TRANSFERASE-DNA complex | ||||||||||||||||||||||||
機能・相同性 | 機能・相同性情報 cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / STING mediated induction of host immune responses / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / regulation of immunoglobulin production / cGAS/STING signaling pathway / regulation of T cell activation / pattern recognition receptor signaling pathway / cytoplasmic pattern recognition receptor signaling pathway ...cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / STING mediated induction of host immune responses / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / regulation of immunoglobulin production / cGAS/STING signaling pathway / regulation of T cell activation / pattern recognition receptor signaling pathway / cytoplasmic pattern recognition receptor signaling pathway / negative regulation of cGAS/STING signaling pathway / cGMP-mediated signaling / cellular response to exogenous dsRNA / negative regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of type I interferon production / negative regulation of megakaryocyte differentiation / nucleosome binding / negative regulation of double-strand break repair via homologous recombination / protein localization to CENP-A containing chromatin / Chromatin modifying enzymes / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / Packaging Of Telomere Ends / positive regulation of defense response to virus by host / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / Deposition of new CENPA-containing nucleosomes at the centromere / nucleosomal DNA binding / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / phosphatidylinositol-4,5-bisphosphate binding / Inhibition of DNA recombination at telomere / activation of innate immune response / telomere organization / Meiotic synapsis / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / Interleukin-7 signaling / RNA Polymerase I Promoter Opening / cAMP-mediated signaling / epigenetic regulation of gene expression / Assembly of the ORC complex at the origin of replication / Regulation of endogenous retroelements by KRAB-ZFP proteins / SUMOylation of chromatin organization proteins / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / DNA methylation / Condensation of Prophase Chromosomes / HCMV Late Events / SIRT1 negatively regulates rRNA expression / Chromatin modifications during the maternal to zygotic transition (MZT) / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / innate immune response in mucosa / PRC2 methylates histones and DNA / Defective pyroptosis / determination of adult lifespan / HDACs deacetylate histones / RNA Polymerase I Promoter Escape / lipopolysaccharide binding / Nonhomologous End-Joining (NHEJ) / Transcriptional regulation by small RNAs / molecular condensate scaffold activity / Formation of the beta-catenin:TCF transactivating complex / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / NoRC negatively regulates rRNA expression / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / G2/M DNA damage checkpoint / HDMs demethylate histones / B-WICH complex positively regulates rRNA expression / DNA Damage/Telomere Stress Induced Senescence / heterochromatin formation / PKMTs methylate histone lysines / Metalloprotease DUBs / Meiotic recombination / Pre-NOTCH Transcription and Translation / RMTs methylate histone arginines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / Transcriptional regulation of granulopoiesis / structural constituent of chromatin / positive regulation of cellular senescence / UCH proteinases / antimicrobial humoral immune response mediated by antimicrobial peptide / nucleosome / nucleosome assembly / E3 ubiquitin ligases ubiquitinate target proteins / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / chromatin organization / RUNX1 regulates transcription of genes involved in differentiation of HSCs / antibacterial humoral response / site of double-strand break / Factors involved in megakaryocyte development and platelet production / HATs acetylate histones / gene expression / Processing of DNA double-strand break ends / Senescence-Associated Secretory Phenotype (SASP) / double-stranded DNA binding / Oxidative Stress Induced Senescence / defense response to Gram-negative bacterium / defense response to virus / Estrogen-dependent gene expression / killing of cells of another organism 類似検索 - 分子機能 | ||||||||||||||||||||||||
生物種 | Homo sapiens (ヒト) | ||||||||||||||||||||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 4.9 Å | ||||||||||||||||||||||||
データ登録者 | Cao, D. / Han, X. / Fan, X. / Xu, R.M. / Zhang, X. | ||||||||||||||||||||||||
資金援助 | 中国, 7件
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引用 | ジャーナル: Cell Res / 年: 2020 タイトル: Structural basis for nucleosome-mediated inhibition of cGAS activity. 著者: Duanfang Cao / Xiaonan Han / Xiaoyi Fan / Rui-Ming Xu / Xinzheng Zhang / 要旨: Activation of cyclic GMP-AMP synthase (cGAS) through sensing cytosolic double stranded DNA (dsDNA) plays a pivotal role in innate immunity against exogenous infection as well as cellular regulation ...Activation of cyclic GMP-AMP synthase (cGAS) through sensing cytosolic double stranded DNA (dsDNA) plays a pivotal role in innate immunity against exogenous infection as well as cellular regulation under stress. Aberrant activation of cGAS induced by self-DNA is related to autoimmune diseases. cGAS accumulates at chromosomes during mitosis or spontaneously in the nucleus. Binding of cGAS to the nucleosome competitively attenuates the dsDNA-mediated cGAS activation, but the molecular mechanism of the attenuation is still poorly understood. Here, we report two cryo-electron microscopy structures of cGAS-nucleosome complexes. The structures reveal that cGAS interacts with the nucleosome as a monomer, forming 1:1 and 2:2 complexes, respectively. cGAS contacts the nucleosomal acidic patch formed by the H2A-H2B heterodimer through the dsDNA-binding site B in both complexes, and could interact with the DNA from the other symmetrically placed nucleosome via the dsDNA-binding site C in the 2:2 complex. The bound nucleosome inhibits the activation of cGAS through blocking the interaction of cGAS with ligand dsDNA and disrupting cGAS dimerization. R236A or R255A mutation of cGAS impairs the binding between cGAS and the nucleosome, and largely relieves the nucleosome-mediated inhibition of cGAS activity. Our study provides structural insights into the inhibition of cGAS activity by the nucleosome, and advances the understanding of the mechanism by which hosts avoid the autoimmune attack caused by cGAS. | ||||||||||||||||||||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | 分子: MolmilJmol/JSmol |
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 7ccr.cif.gz | 667.2 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb7ccr.ent.gz | 523.2 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 7ccr.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 7ccr_validation.pdf.gz | 908.2 KB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 7ccr_full_validation.pdf.gz | 939.9 KB | 表示 | |
XML形式データ | 7ccr_validation.xml.gz | 64.6 KB | 表示 | |
CIF形式データ | 7ccr_validation.cif.gz | 108.1 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/cc/7ccr ftp://data.pdbj.org/pub/pdb/validation_reports/cc/7ccr | HTTPS FTP |
-関連構造データ
-リンク
-集合体
登録構造単位 |
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-要素
-タンパク質 , 5種, 18分子 AELPBFMQCGNRDHOSKV
#1: タンパク質 | 分子量: 11504.476 Da / 分子数: 4 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) 遺伝子: H3C1, H3FA, HIST1H3A, H3C2, H3FL, HIST1H3B, H3C3, H3FC HIST1H3C, H3C4, H3FB, HIST1H3D, H3C6, H3FD, HIST1H3E, H3C7, H3FI, HIST1H3F, H3C8, H3FH, HIST1H3G, H3C10, H3FK, HIST1H3H, H3C11, H3FF, ...遺伝子: H3C1, H3FA, HIST1H3A, H3C2, H3FL, HIST1H3B, H3C3, H3FC HIST1H3C, H3C4, H3FB, HIST1H3D, H3C6, H3FD, HIST1H3E, H3C7, H3FI, HIST1H3F, H3C8, H3FH, HIST1H3G, H3C10, H3FK, HIST1H3H, H3C11, H3FF, HIST1H3I, H3C12, H3FJ, HIST1H3J 発現宿主: Escherichia coli (大腸菌) / 参照: UniProt: P68431 #2: タンパク質 | 分子量: 9067.586 Da / 分子数: 4 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Escherichia coli (大腸菌) / 参照: UniProt: P62805*PLUS #3: タンパク質 | 分子量: 11308.161 Da / 分子数: 4 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: H2AC4, H2AFM, HIST1H2AB, H2AC8, H2AFA, HIST1H2AE / 発現宿主: Escherichia coli (大腸菌) / 参照: UniProt: P04908 #4: タンパク質 | 分子量: 10334.827 Da / 分子数: 4 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: H2BC11, H2BFR, HIST1H2BJ / 発現宿主: Escherichia coli (大腸菌) / 参照: UniProt: P06899 #7: タンパク質 | 分子量: 42759.270 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: CGAS, C6orf150, MB21D1 / 発現宿主: Escherichia coli (大腸菌) / 参照: UniProt: Q8N884, cyclic GMP-AMP synthase |
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-DNA鎖 , 2種, 4分子 ITJU
#5: DNA鎖 | 分子量: 45604.047 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Escherichia coli (大腸菌) #6: DNA鎖 | 分子量: 45145.754 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Escherichia coli (大腸菌) |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
-試料調製
構成要素 | 名称: the cGAS-nucleosome complex in 2:2 molar ratio / タイプ: COMPLEX / Entity ID: all / 由来: RECOMBINANT |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Escherichia coli (大腸菌) |
緩衝液 | pH: 7.5 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
-電子顕微鏡撮影
実験機器 | モデル: Talos Arctica / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TECNAI ARCTICA |
電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 200 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD |
撮影 | 電子線照射量: 50 e/Å2 フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
-解析
ソフトウェア | 名称: PHENIX / バージョン: 1.12_2829: / 分類: 精密化 | ||||||||||||||||||||||||
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3次元再構成 | 解像度: 4.9 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 107374 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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