+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-13676 | |||||||||
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タイトル | Human SMG1-8-9 kinase complex bound to a SMG1 inhibitor - SMG1 body | |||||||||
マップデータ | ||||||||||
試料 |
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機能・相同性 | 機能・相同性情報 diacylglycerol-dependent serine/threonine kinase activity / chromatoid body / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / regulation of telomere maintenance / telomeric DNA binding / phosphatidylinositol phosphate biosynthetic process / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / mRNA export from nucleus / peptidyl-serine phosphorylation / protein autophosphorylation ...diacylglycerol-dependent serine/threonine kinase activity / chromatoid body / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / regulation of telomere maintenance / telomeric DNA binding / phosphatidylinositol phosphate biosynthetic process / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / mRNA export from nucleus / peptidyl-serine phosphorylation / protein autophosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / DNA repair / protein serine kinase activity / protein serine/threonine kinase activity / DNA damage response / RNA binding / nucleoplasm / ATP binding / nucleus / metal ion binding / cytoplasm / cytosol 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: 3.05 Å | |||||||||
データ登録者 | Langer LM / Conti E | |||||||||
資金援助 | ドイツ, 1件
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引用 | ジャーナル: Elife / 年: 2021 タイトル: Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8. 著者: Lukas M Langer / Fabien Bonneau / Yair Gat / Elena Conti / 要旨: The PI3K-related kinase (PIKK) SMG1 monitors the progression of metazoan nonsense-mediated mRNA decay (NMD) by phosphorylating the RNA helicase UPF1. Previous work has shown that the activity of SMG1 ...The PI3K-related kinase (PIKK) SMG1 monitors the progression of metazoan nonsense-mediated mRNA decay (NMD) by phosphorylating the RNA helicase UPF1. Previous work has shown that the activity of SMG1 is impaired by small molecule inhibitors, is reduced by the SMG1 interactors SMG8 and SMG9, and is downregulated by the so-called SMG1 insertion domain. However, the molecular basis for this complex regulatory network has remained elusive. Here, we present cryo-electron microscopy reconstructions of human SMG1-9 and SMG1-8-9 complexes bound to either a SMG1 inhibitor or a non-hydrolyzable ATP analog at overall resolutions ranging from 2.8 to 3.6 Å. These structures reveal the basis with which a small molecule inhibitor preferentially targets SMG1 over other PIKKs. By comparison with our previously reported substrate-bound structure (Langer et al.,2020), we show that the SMG1 insertion domain can exert an autoinhibitory function by directly blocking the substrate-binding path as well as overall access to the SMG1 kinase active site. Together with biochemical analysis, our data indicate that SMG1 autoinhibition is stabilized by the presence of SMG8. Our results explain the specific inhibition of SMG1 by an ATP-competitive small molecule, provide insights into regulation of its kinase activity within the NMD pathway, and expand the understanding of PIKK regulatory mechanisms in general. | |||||||||
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 | EMマップ: SurfViewMolmilJmol/JSmol |
添付画像 |
-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_13676.map.gz | 3.3 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-13676-v30.xml emd-13676.xml | 13.3 KB 13.3 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_13676.png | 49.7 KB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-13676 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-13676 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_13676_validation.pdf.gz | 303.7 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_13676_full_validation.pdf.gz | 303.3 KB | 表示 | |
XML形式データ | emd_13676_validation.xml.gz | 7.1 KB | 表示 | |
CIF形式データ | emd_13676_validation.cif.gz | 8.1 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13676 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13676 | HTTPS FTP |
-関連構造データ
-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_13676.map.gz / 形式: CCP4 / 大きさ: 216 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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ボクセルのサイズ | X=Y=Z: 0.8512 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
-試料の構成要素
-全体 : SMG1-SMG8-SMG9 kinase complex bound to a SMG1 inhibitor
全体 | 名称: SMG1-SMG8-SMG9 kinase complex bound to a SMG1 inhibitor |
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要素 |
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-超分子 #1: SMG1-SMG8-SMG9 kinase complex bound to a SMG1 inhibitor
超分子 | 名称: SMG1-SMG8-SMG9 kinase complex bound to a SMG1 inhibitor タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1 |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
組換発現 | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 597 KDa |
-分子 #1: Serine/threonine-protein kinase SMG1,Serine/threonine-protein kin...
分子 | 名称: Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase ...名称: Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1 タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO / EC番号: non-specific serine/threonine protein kinase |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 320.901969 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: ANTLVEDVNI CLQACSSLHA LSSSLPDDLL QRCVDVCRVQ LVHSGTRIRQ AFGKLLKSIP LDVVLSNNNH TEIQEISLAL RSHMSKAPS NTFHPQDFSD VISFILYGNS HRTGKDNWLE RLFYSCQRLD KRDQSTIPRN LLKTDAVLWQ WAIWEAAQFT V LSKLRTPL ...文字列: ANTLVEDVNI CLQACSSLHA LSSSLPDDLL QRCVDVCRVQ LVHSGTRIRQ AFGKLLKSIP LDVVLSNNNH TEIQEISLAL RSHMSKAPS NTFHPQDFSD VISFILYGNS HRTGKDNWLE RLFYSCQRLD KRDQSTIPRN LLKTDAVLWQ WAIWEAAQFT V LSKLRTPL GRAQDTFQTI EGIIRSLAAH TLNPDQDVSQ WTTADNDEGH GNNQLRLVLL LQYLENLEKL MYNAYEGCAN AL TSPPKVI RTFFYTNRQT CQDWLTRIRL SIMRVGLLAG QPAVTVRHGF DLLTEMKTTS LSQGNELEVT IMMVVEALCE LHC PEAIQG IAVWSSSIVG KNLLWINSVA QQAEGRFEKA SVEYQEHLCA MTGVDCCISS FDKSVLTLAN AGRNSASPKH SLNG ESRKT VLSKPTDSSP EVINYLGNKA CECYISIADW AAVQEWQNSI HDLKKSTSST SLNLKADFNY IKSLSSFESG KFVEC TEQL ELLPGENINL LAGGSKEKIN MKKLLPNMLS PDPRELQKSI EVQLLRSSVC LATALNPIEQ DQKWQSITEN VVKYLK QTS RIAIGPLRLS TLTVSQSLPV LSTLQLYCSS ALENTVSNRL STEDCLIPLF SEALRSCKQH DVRPWMQALR YTMYQNQ LL EKIKEQTVPI RSHLMELGLT AAKFARKRGN VSLATRLLAQ CSEVQLGKTT TAQDLVQHFK KLSTQGQVDE KWGPELDI E KTKLLYTAGQ STHAMEMLSS CAISFCKSVK AEYAVAKSIL TLAKWIQAEW KEISGQLKQV YRAQHQQNFT GLSTLSKNI LTLIELPSVN TMEEEYPRIE SESTVHIGVG EPDFILGQLY HLSSVQAPEV AKSWAALASW AYRWGRKVVD NAS(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)EGV IKVWRKVVDR IFSLYKLSCS AYFTFLKLNA GQIPLDEDDP RL HLSHRVE QSTDDMIVMA TLRLLRLLVK HAGELRQYLE HGLETTPTAP WRGIIPQLFS RLNHPEVYVR QSICNLLCRV AQD SPHLIL YPAIVGTISL SSESQASGNK FSTAIPTLLG NIQGEELLVS ECEGGSPPAS QDSNKDEPKS GLNEDQAMMQ DCYS KIVDK LSSANPTMVL QVQMLVAELR RVTVLWDELW LGVLLQQHMY VL(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)PHEKWFQD NYGDAIENAL EKLK(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)YIL RLEEISPWLA AMTNTEIALP GEVSARDTVT IHSVGGTITI LPTKTKP KK LLFLGSDGKS YPYLFKGLED LHLDERIMQF LSIVNTMFAT INRQETPRFH ARHYSVTPLG TRSGLIQWVD GATPLFGL Y KRWQQREAAL QAQKAQDSYQ TPQNPGIVPR PSELYYSKIG PALKTVGLSL DVSRRDWPLH VMKAVLEELM EATPPNLLA KELWSSCTTP DEWWRVTQSY ARSTAVMSMV GYIIGLGDRH LDNVLIDMTT GEVVHIDYNV CFEKGKSLRV PEKVPFRMTQ NIETALGVT GVEGVFRLSC EQVLHIMRRG RETLLTLLEA FVYDPLVDWT AGGEAGFAGA VYGGGGQQAE SKQSKREMER E ITRSLFSS RVAEIKVNWF KNRDEMLVVL PKLDGSLDEY LSLQEQLTDV EKLQGKLLEE IEFLEGAEGV DHPSHTLQHR YS EHTQLQT QQRAVQEAIQ VKLNEFEQWI THYQAAFNNL EATQLASLLQ EISTQMDLGP PSYVPATAFL QNAGQAHLIS QCE QLEGEV GALLQQRRSV LRGCLEQLHH YATVALQYPK AIFQKHRIEQ WKTWMEELIC NTTVERCQEL YRKYEMQYAP QPPP TVCQF ITATEMTLQR YAADINSRLI RQVERLKQEA VTVPVCEDQL KEIERCIKVF LHENGEEGSL SLASVIISAL CTLTR RNLM MEGAASSAGE QLVDLTSRDG AWFLEELCSM SGNVTCLVQL LKQCHLVPQD LDIPNPMEAS ETVHLANGVY TSLQEL NSN FRQIIFPEAL RCLMKGEYTL ESMLHELDGL IEQTTDGVPL QTLVESLQAY LRNAAMGLEE ETHAHYIDVA RLLHAQY GE LIQPRNGSVD ETPKMSAGQM LLVAFDGMFA QVETAFSLLV EKLNKMEIPI AWRKIDIIRE ARSTQVNFFD DDNHRQVL E EIFFLKRLQT IKEFFRLCGT FSKTLSGSSS LEDQNTVNGP VQIVNVKTLF RNSCFSEDQM AKPIKAFTAD FVRQLLIGL PNQALGLTLC SFISALGVDI IAQVEAKDFG AESKVSVDDL CKKAVEHNIQ IGKFSQLVMN RATVLASSYD TAWKKHDLVR RLETSISSC KTSLQRVQLH IAMFQWQHED LLINRPQAMS VTPPPRSAIL TSMKKKLHTL SQIETSIATV QEKLAALESS I EQRLKWAG GANPALAPVL QDFEATIAER RNLVLKESQR ASQVTFLCSN IIHFESLRTR TAEALNLDAA LFELIKRCQQ MC SFASQFN SSVSELELRL LQRVDTGLEH PIGSSEWLLS AHKQLTQDMS TQRAIQTEKE QQIETVCETI QNLVDNIKTV LTG HNRQLG DVKHLLKAMA KDEEAALADG EDVPYENSVR QFLGEYKSWQ DNIQTVLFTL VQAMGQVRSQ EHVEMLQEIT PTLK ELKTQ SQSIYNNLVS FASPLVTDAT NECSSPTSSA TYQPSFAAAV RSNTGQKTQP DVMSQNARKL IQKNLATSAD TPPST VPGT GKSVACSPKK AVRDPKTGKA VQERNSYAVS VWKRVKAKLE GRDVDPNRRM SVAEQVDYVI KEATNLDNLA QLYEGW TAW V |
-分子 #2: INOSITOL HEXAKISPHOSPHATE
分子 | 名称: INOSITOL HEXAKISPHOSPHATE / タイプ: ligand / ID: 2 / コピー数: 1 / 式: IHP |
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分子量 | 理論値: 660.035 Da |
Chemical component information | ChemComp-IHP: |
-分子 #3: 1-[4-[4-[2-[[4-chloranyl-3-(diethylsulfamoyl)phenyl]amino]pyrimid...
分子 | 名称: 1-[4-[4-[2-[[4-chloranyl-3-(diethylsulfamoyl)phenyl]amino]pyrimidin-4-yl]pyridin-2-yl]phenyl]-3-methyl-urea タイプ: ligand / ID: 3 / コピー数: 1 / 式: 88C |
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分子量 | 理論値: 566.074 Da |
Chemical component information | ChemComp-88C: |
-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-PROPANE |
-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 (6k x 4k) / 平均電子線量: 89.32 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 |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
-画像解析
最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 3.05 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 228291 |
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初期 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |