+
データを開く
-
基本情報
登録情報 | データベース: PDB / ID: 9dwu | ||||||
---|---|---|---|---|---|---|---|
タイトル | CoREST complex bound to U2AF2 | ||||||
![]() |
| ||||||
![]() | GENE REGULATION / RNA / splicing / melanoma / epigenetics | ||||||
機能・相同性 | ![]() U2AF complex / poly-pyrimidine tract binding / pre-mRNA 3'-splice site binding / positive regulation of megakaryocyte differentiation / guanine metabolic process / negative regulation of transcription initiation-coupled chromatin remodeling / protein demethylation / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / demethylase activity ...U2AF complex / poly-pyrimidine tract binding / pre-mRNA 3'-splice site binding / positive regulation of megakaryocyte differentiation / guanine metabolic process / negative regulation of transcription initiation-coupled chromatin remodeling / protein demethylation / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / demethylase activity / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / neuron maturation / muscle cell development / positive regulation of neural precursor cell proliferation / mRNA 3'-end processing / C2H2 zinc finger domain binding / MRF binding / regulation of androgen receptor signaling pathway / commitment complex / Transport of Mature mRNA derived from an Intron-Containing Transcript / DNA repair complex / negative regulation of DNA binding / RNA Polymerase II Transcription Termination / U2-type prespliceosome / molecular function inhibitor activity / nuclear androgen receptor binding / regulation of double-strand break repair via homologous recombination / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of neuroblast proliferation / DNA repair-dependent chromatin remodeling / positive regulation of stem cell proliferation / spliceosomal complex assembly / histone H3K9 demethylase activity / histone methyltransferase complex / negative regulation of DNA damage response, signal transduction by p53 class mediator / Protein hydroxylation / negative regulation of mRNA splicing, via spliceosome / histone deacetylase complex / histone demethylase activity / positive regulation of cell size / positive regulation of epithelial to mesenchymal transition / response to fungicide / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / negative regulation of protein binding / cellular response to cAMP / negative regulation of protein ubiquitination / transcription repressor complex / negative regulation of DNA-binding transcription factor activity / mRNA Splicing - Major Pathway / positive regulation of RNA splicing / epigenetic regulation of gene expression / Regulation of PTEN gene transcription / positive regulation of protein ubiquitination / erythrocyte differentiation / HDACs deacetylate histones / spliceosomal complex / promoter-specific chromatin binding / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / cellular response to gamma radiation / HDMs demethylate histones / cerebral cortex development / mRNA splicing, via spliceosome / positive regulation of neuron projection development / mRNA processing / cellular response to UV / transcription corepressor activity / p53 binding / flavin adenine dinucleotide binding / regulation of protein localization / positive regulation of cold-induced thermogenesis / Factors involved in megakaryocyte development and platelet production / chromatin organization / transcription regulator complex / DNA-binding transcription factor binding / Estrogen-dependent gene expression / RNA polymerase II-specific DNA-binding transcription factor binding / Potential therapeutics for SARS / transcription coactivator activity / chromosome, telomeric region / oxidoreductase activity / nuclear speck / negative regulation of gene expression / negative regulation of DNA-templated transcription / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / enzyme binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / RNA binding / nucleoplasm / identical protein binding / nucleus 類似検索 - 分子機能 | ||||||
生物種 | ![]() | ||||||
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: 5.14 Å | ||||||
![]() | Hicks, C.W. / Alani, R.M. | ||||||
資金援助 | ![]()
| ||||||
![]() | ![]() タイトル: CoREST Complex Inhibition Alters RNA Splicing to Promote Neoantigen Expression and Enhance Tumor Immunity. 著者: Robert J Fisher / Kihyun Park / Kwangwoon Lee / Katarina Pinjusic / Allison Vanasse / Christina S Ennis / Scott Ficcaro / Jarrod Marto / Stephanie Stransky / Joseph Duke-Cohan / Anupa ...著者: Robert J Fisher / Kihyun Park / Kwangwoon Lee / Katarina Pinjusic / Allison Vanasse / Christina S Ennis / Scott Ficcaro / Jarrod Marto / Stephanie Stransky / Joseph Duke-Cohan / Anupa Geethadevi / Eric Raabe / Simone Sidoli / Chad W Hicks / Derin B Keskin / Catherine J Wu / Philip A Cole / Rhoda M Alani 要旨: Epigenetic complexes tightly regulate gene expression and colocalize with RNA splicing machinery; however, the consequences of these interactions are uncertain. Here, we identify unique interactions ...Epigenetic complexes tightly regulate gene expression and colocalize with RNA splicing machinery; however, the consequences of these interactions are uncertain. Here, we identify unique interactions of the CoREST repressor complex with RNA splicing factors and their functional consequences in tumorigenesis. Using mass spectrometry, in vivo binding assays, and cryo-EM we find that CoREST complex-splicing factor interactions are direct and perturbed by the CoREST complex inhibitor, corin, leading to extensive changes in RNA splicing in melanoma and other malignancies. Using predictive machine learning models and MHC IP-MS, we identify thousands of corin-induced neopeptides derived from unannotated splice sites which generate immunogenic splice-neoantigens. Furthermore, corin reactivates the response to immune checkpoint blockade and promotes dramatic expansion of cytotoxic T cells in an immune cold melanoma model. CoREST complex inhibition thus represents a unique therapeutic opportunity in cancer which creates tumor-associated neoantigens that enhance the immunogenicity of current therapeutics. STATEMENT OF SIGNIFICANCE: We identify a novel role of the CoREST transcriptional repressor complex in regulating pre-mRNA splicing and find that the small molecule inhibitor, corin, promotes ...STATEMENT OF SIGNIFICANCE: We identify a novel role of the CoREST transcriptional repressor complex in regulating pre-mRNA splicing and find that the small molecule inhibitor, corin, promotes alternative splicing events in cancer leading to neoantigen expression and T cell-mediated immunity. This represents a potential approach to promote immunoreactive neoantigen expression in immune-cold tumors. | ||||||
履歴 |
|
-
構造の表示
構造ビューア | 分子: ![]() ![]() |
---|
-
ダウンロードとリンク
-
ダウンロード
PDBx/mmCIF形式 | ![]() | 179.5 KB | 表示 | ![]() |
---|---|---|---|---|
PDB形式 | ![]() | 140.1 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 1.4 MB | 表示 | ![]() |
---|---|---|---|---|
文書・詳細版 | ![]() | 1.4 MB | 表示 | |
XML形式データ | ![]() | 41.5 KB | 表示 | |
CIF形式データ | ![]() | 60.5 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 47265MC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 ( |
---|---|
類似構造データ | 類似検索 - 機能・相同性 ![]() |
-
リンク
-
集合体
登録構造単位 | ![]()
|
---|---|
1 |
|
-
要素
#1: タンパク質 | 分子量: 74126.781 Da / 分子数: 1 / 断片: UNP residues 171-836 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
---|---|
#2: タンパク質 | 分子量: 7675.833 Da / 分子数: 1 / 断片: UNP residues 311-379 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
#3: タンパク質 | 分子量: 8641.860 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
Has protein modification | N |
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
---|---|
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: Splicing factor U2AF2 bound to the CoREST complex made up of LSD1 and RCOR1 タイプ: COMPLEX / Entity ID: all / 由来: RECOMBINANT |
---|---|
由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() |
緩衝液 | pH: 8 |
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
顕微鏡 | モデル: TFS GLACIOS |
---|---|
電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2500 nm / 最小 デフォーカス(公称値): 1000 nm |
撮影 | 電子線照射量: 50 e/Å2 フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) |
-
解析
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION |
---|---|
3次元再構成 | 解像度: 5.14 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 172429 / 対称性のタイプ: POINT |