+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-42247 | |||||||||
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タイトル | Degrader-induced complex between PTPN2 and CRBN-DDB1 | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | HYDROLASE | |||||||||
機能・相同性 | 機能・相同性情報 negative regulation of interleukin-2-mediated signaling pathway / negative regulation of interleukin-4-mediated signaling pathway / negative regulation of positive thymic T cell selection / positive regulation of PERK-mediated unfolded protein response / negative regulation of platelet-derived growth factor receptor-beta signaling pathway / negative regulation of macrophage colony-stimulating factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / negative regulation of macrophage differentiation / regulation of type II interferon-mediated signaling pathway / negative regulation of chemotaxis ...negative regulation of interleukin-2-mediated signaling pathway / negative regulation of interleukin-4-mediated signaling pathway / negative regulation of positive thymic T cell selection / positive regulation of PERK-mediated unfolded protein response / negative regulation of platelet-derived growth factor receptor-beta signaling pathway / negative regulation of macrophage colony-stimulating factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / negative regulation of macrophage differentiation / regulation of type II interferon-mediated signaling pathway / negative regulation of chemotaxis / negative regulation of tyrosine phosphorylation of STAT protein / negative regulation of monoatomic ion transmembrane transport / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / negative regulation of receptor signaling pathway via JAK-STAT / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / Interleukin-37 signaling / biological process involved in interaction with symbiont / syntaxin binding / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex / negative regulation of type I interferon-mediated signaling pathway / ubiquitin ligase complex scaffold activity / Cul4B-RING E3 ubiquitin ligase complex / negative regulation of T cell receptor signaling pathway / STAT family protein binding / regulation of hepatocyte growth factor receptor signaling pathway / insulin receptor recycling / negative regulation of reproductive process / negative regulation of developmental process / negative regulation of epidermal growth factor receptor signaling pathway / negative regulation of type II interferon-mediated signaling pathway / locomotory exploration behavior / cullin family protein binding / viral release from host cell / endoplasmic reticulum-Golgi intermediate compartment / negative regulation of lipid storage / T cell differentiation / non-membrane spanning protein tyrosine phosphatase activity / peptidyl-tyrosine dephosphorylation / positive regulation of Wnt signaling pathway / negative regulation of tumor necrosis factor-mediated signaling pathway / ectopic germ cell programmed cell death / proteasomal protein catabolic process / negative regulation of protein-containing complex assembly / positive regulation of viral genome replication / Regulation of IFNG signaling / positive regulation of gluconeogenesis / negative regulation of insulin receptor signaling pathway / B cell differentiation / protein-tyrosine-phosphatase / erythrocyte differentiation / protein tyrosine phosphatase activity / endosome lumen / nucleotide-excision repair / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / positive regulation of protein-containing complex assembly / PKR-mediated signaling / regulation of circadian rhythm / Negative regulation of MET activity / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Dual Incision in GG-NER / Wnt signaling pathway / receptor tyrosine kinase binding / negative regulation of ERK1 and ERK2 cascade / negative regulation of inflammatory response / Formation of Incision Complex in GG-NER / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / positive regulation of protein catabolic process / cellular response to UV / integrin binding / rhythmic process / insulin receptor signaling pathway / glucose homeostasis / Neddylation / protein-macromolecule adaptor activity / site of double-strand break / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / Potential therapeutics for SARS / damaged DNA binding / chromosome, telomeric region / protein ubiquitination / negative regulation of cell population proliferation / DNA repair / DNA damage response / protein-containing complex binding / nucleolus / negative regulation of apoptotic process / apoptotic process / protein kinase binding / perinuclear region of cytoplasm 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.3 Å | |||||||||
データ登録者 | Catalano C / Bratkowski M / Scapin G / Hao Q | |||||||||
資金援助 | 1件
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引用 | ジャーナル: Commun Chem / 年: 2024 タイトル: Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex. 著者: Qi Hao / Manoj K Rathinaswamy / Kelly L Klinge / Matthew Bratkowski / Amirhossein Mafi / Christina K Baumgartner / Keith M Hamel / Gesine K Veits / Rinku Jain / Claudio Catalano / Mark ...著者: Qi Hao / Manoj K Rathinaswamy / Kelly L Klinge / Matthew Bratkowski / Amirhossein Mafi / Christina K Baumgartner / Keith M Hamel / Gesine K Veits / Rinku Jain / Claudio Catalano / Mark Fitzgerald / Alexander W Hird / Eunice Park / Harit U Vora / James A Henderson / Kenton Longenecker / Charles W Hutchins / Wei Qiu / Giovanna Scapin / Qi Sun / Vincent S Stoll / Chaohong Sun / Ping Li / Dan Eaton / David Stokoe / Stewart L Fisher / Christopher G Nasveschuk / Marcia Paddock / Michael E Kort / 要旨: PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in ...PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4, and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes. | |||||||||
履歴 |
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-構造の表示
添付画像 |
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-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_42247.map.gz | 167.9 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-42247-v30.xml emd-42247.xml | 19.1 KB 19.1 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_42247.png | 38.1 KB | ||
マスクデータ | emd_42247_msk_1.map | 178 MB | マスクマップ | |
Filedesc metadata | emd-42247.cif.gz | 7.2 KB | ||
その他 | emd_42247_half_map_1.map.gz emd_42247_half_map_2.map.gz | 165 MB 165 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-42247 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-42247 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_42247_validation.pdf.gz | 1.2 MB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_42247_full_validation.pdf.gz | 1.2 MB | 表示 | |
XML形式データ | emd_42247_validation.xml.gz | 14.6 KB | 表示 | |
CIF形式データ | emd_42247_validation.cif.gz | 17 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-42247 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-42247 | HTTPS FTP |
-関連構造データ
関連構造データ | 8uh6MC 8u0hC M: このマップから作成された原子モデル C: 同じ文献を引用 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_42247.map.gz / 形式: CCP4 / 大きさ: 178 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 0.834 Å | ||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-マスク #1
ファイル | emd_42247_msk_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #2
ファイル | emd_42247_half_map_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_42247_half_map_2.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-試料の構成要素
-全体 : CRBN-DDB1-PTPN2 complex
全体 | 名称: CRBN-DDB1-PTPN2 complex |
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要素 |
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-超分子 #1: CRBN-DDB1-PTPN2 complex
超分子 | 名称: CRBN-DDB1-PTPN2 complex / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#3 |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 217.81996 KDa |
-分子 #1: DNA damage-binding protein 1
分子 | 名称: DNA damage-binding protein 1 / タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 128.33382 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: MHHHHHHHHM SYNYVVTAQK PTAVNGCVTG HFTSAEDLNL LIAKNTRLEI YVVTAEGLRP VKEVGMYGKI AVMELFRPKG ESKDLLFIL TAKYNACILE YKQSGESIDI ITRAHGNVQD RIGRPSETGI IGIIDPECRM IGLRLYDGLF KVIPLDRDNK E LKAFNIRL ...文字列: MHHHHHHHHM SYNYVVTAQK PTAVNGCVTG HFTSAEDLNL LIAKNTRLEI YVVTAEGLRP VKEVGMYGKI AVMELFRPKG ESKDLLFIL TAKYNACILE YKQSGESIDI ITRAHGNVQD RIGRPSETGI IGIIDPECRM IGLRLYDGLF KVIPLDRDNK E LKAFNIRL EELHVIDVKF LYGCQAPTIC FVYQDPQGRH VKTYEVSLRE KEFNKGPWKQ ENVEAEASMV IAVPEPFGGA II IGQESIT YHNGDKYLAI APPIIKQSTI VCHNRVDPNG SRYLLGDMEG RLFMLLLEKE EQMDGTVTLK DLRVELLGET SIA ECLTYL DNGVVFVGSR LGDSQLVKLN VDSNEQGSYV VAMETFTNLG PIVDMCVVDL ERQGQGQLVT CSGAFKEGSL RIIR NGIGI HEHASIDLPG IKGLWPLRSD PNRETDDTLV LSFVGQTRVL MLNGEEVEET ELMGFVDDQQ TFFCGNVAHQ QLIQI TSAS VRLVSQEPKA LVSEWKEPQA KNISVASCNS SQVVVAVGRA LYYLQIHPQE LRQISHTEME HEVACLDITP LGDSNG LSP LCAIGLWTDI SARILKLPSF ELLHKEMLGG EIIPRSILMT TFESSHYLLC ALGDGALFYF GLNIETGLLS DRKKVTL GT QPTVLRTFRS LSTTNVFACS DRPTVIYSSN HKLVFSNVNL KEVNYMCPLN SDGYPDSLAL ANNSTLTIGT IDEIQKLH I RTVPLYESPR KICYQEVSQC FGVLSSRIEV QDTSGGTTAL RPSASTQALS SSVSSSKLFS SSTAPHETSF GEEVEVHNL LIIDQHTFEV LHAHQFLQNE YALSLVSCKL GKDPNTYFIV GTAMVYPEEA EPKQGRIVVF QYSDGKLQTV AEKEVKGAVY SMVEFNGKL LASINSTVRL YEWTTEKELR TECNHYNNIM ALYLKTKGDF ILVGDLMRSV LLLAYKPMEG NFEEIARDFN P NWMSAVEI LDDDNFLGAE NAFNLFVCQK DSAATTDEER QHLQEVGLFH LGEFVNVFCH GSLVMQNLGE TSTPTQGSVL FG TVNGMIG LVTSLSESWY NLLLDMQNRL NKVIKSVGKI EHSFWRSFHT ERKTEPATGF IDGDLIESFL DISRPKMQEV VAN LQYDDG SGMKREATAD DLIKVVEELT RIH UniProtKB: DNA damage-binding protein 1 |
-分子 #2: Protein cereblon
分子 | 名称: Protein cereblon / タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 51.77702 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: MWSHPQFEKM AGEGDQQDAA HNMGNHLPLL PAESEEEDEM EVEDQDSKEA KKPNIINFDT SLPTSHTYLG ADMEEFHGRT LHDDDSCQV IPVLPQVMMI LIPGQTLPLQ LFHPQEVSMV RNLIQKDRTF AVLAYSNVQE REAQFGTTAE IYAYREEQDF G IEIVKVKA ...文字列: MWSHPQFEKM AGEGDQQDAA HNMGNHLPLL PAESEEEDEM EVEDQDSKEA KKPNIINFDT SLPTSHTYLG ADMEEFHGRT LHDDDSCQV IPVLPQVMMI LIPGQTLPLQ LFHPQEVSMV RNLIQKDRTF AVLAYSNVQE REAQFGTTAE IYAYREEQDF G IEIVKVKA IGRQRFKVLE LRTQSDGIQQ AKVQILPECV LPSTMSAVQL ESLNKCQIFP SKPVSREDQC SYKWWQKYQK RK FHCANLT SWPRWLYSLY DAETLMDRIK KQLREWDENL KDDSLPSNPI DFSYRVAACL PIDDVLRIQL LKIGSAIQRL RCE LDIMNK CTSLCCKQCQ ETEITTKNEI FSLSLCGPMA AYVNPHGYVH ETLTVYKACN LNLIGRPSTE HSWFPGYAWT VAQC KICAS HIGWKFTATK KDMSPQKFWG LTRSALLPTI PDTEDEISPD KVILCL UniProtKB: Protein cereblon |
-分子 #3: Tyrosine-protein phosphatase non-receptor type 2
分子 | 名称: Tyrosine-protein phosphatase non-receptor type 2 / タイプ: protein_or_peptide / ID: 3 / コピー数: 1 / 光学異性体: LEVO / EC番号: protein-tyrosine-phosphatase |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 37.966 KDa |
組換発現 | 生物種: Escherichia coli (大腸菌) |
配列 | 文字列: MAMPTTIERE FEELDTQRRW QPLYLEIRNE SHDYPHRVAK FPENRNRNRY RDVSPYDHSR VKLQNAENDY INASLVDIEE AQRSYILTQ GPLPNTCCHF WLMVWQQKTK AVVMLNRIVE KESVKCAQYW PTDDQEMLFK ETGFSVKLLS EDVKSYYTVH L LQLENINS ...文字列: MAMPTTIERE FEELDTQRRW QPLYLEIRNE SHDYPHRVAK FPENRNRNRY RDVSPYDHSR VKLQNAENDY INASLVDIEE AQRSYILTQ GPLPNTCCHF WLMVWQQKTK AVVMLNRIVE KESVKCAQYW PTDDQEMLFK ETGFSVKLLS EDVKSYYTVH L LQLENINS GETRTISHFH YTTWPDFGVP ESPASFLNFL FKVRESGSLN PDHGPAVIHC SAGIGRSGTF SLVDTCLVLM EK GDDINIK QVLLNMRKYR MGLIQTPDQL RFSYMAIIEG AKCIKGDSSI QKRWKELSKE DLSPAFDHSP NKIMTEKYNH HHH HHHH UniProtKB: Tyrosine-protein phosphatase non-receptor type 2 |
-分子 #4: (5P)-3-(carboxymethoxy)-4-chloro-5-(3-{[(4S)-1-({3-[(4-{1-[(3R)-2...
分子 | 名称: (5P)-3-(carboxymethoxy)-4-chloro-5-(3-{[(4S)-1-({3-[(4-{1-[(3R)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}piperidine-1-carbonyl)amino]phenyl}methanesulfonyl)- ...名称: (5P)-3-(carboxymethoxy)-4-chloro-5-(3-{[(4S)-1-({3-[(4-{1-[(3R)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}piperidine-1-carbonyl)amino]phenyl}methanesulfonyl)-2,2-dimethylpiperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid タイプ: ligand / ID: 4 / コピー数: 1 / 式: WO8 |
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分子量 | 理論値: 976.512 Da |
-分子 #5: ZINC ION
分子 | 名称: ZINC ION / タイプ: ligand / ID: 5 / コピー数: 1 / 式: ZN |
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分子量 | 理論値: 65.409 Da |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
緩衝液 | pH: 7.4 |
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凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) 平均電子線量: 36.09 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2.0 µm / 最小 デフォーカス(公称値): 1.0 µm |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
-画像解析
初期モデル | モデルのタイプ: NONE |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 3.3 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 69542 |
初期 角度割当 | タイプ: RANDOM ASSIGNMENT |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |