+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-0541 | |||||||||
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タイトル | Structure of a MAPK pathway complex | |||||||||
マップデータ | Structure of a MAPK pathway complex | |||||||||
試料 |
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機能・相同性 | 機能・相同性情報 epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / CD4-positive, alpha-beta T cell differentiation / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / labyrinthine layer development / MAP-kinase scaffold activity ...epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / CD4-positive, alpha-beta T cell differentiation / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / labyrinthine layer development / MAP-kinase scaffold activity / type B pancreatic cell proliferation / Signalling to p38 via RIT and RIN / cerebellar cortex formation / head morphogenesis / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / endothelial cell apoptotic process / Signaling by MAP2K mutants / negative regulation of fibroblast migration / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / regulation of Golgi inheritance / spindle pole body / MAP kinase kinase kinase activity / mitogen-activated protein kinase kinase binding / trachea formation / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / positive regulation of axonogenesis / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / stress fiber assembly / protein kinase activator activity / positive regulation of axon regeneration / endodermal cell differentiation / MAPK3 (ERK1) activation / face development / synaptic vesicle exocytosis / somatic stem cell population maintenance / MAP kinase kinase activity / Bergmann glial cell differentiation / thyroid gland development / Uptake and function of anthrax toxins / negative regulation of endothelial cell apoptotic process / Schwann cell development / positive regulation of substrate adhesion-dependent cell spreading / keratinocyte differentiation / Signal transduction by L1 / positive regulation of stress fiber assembly / response to cAMP / cellular response to calcium ion / ERK1 and ERK2 cascade / protein serine/threonine/tyrosine kinase activity / myelination / substrate adhesion-dependent cell spreading / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / insulin-like growth factor receptor signaling pathway / cellular response to nerve growth factor stimulus / thymus development / epidermal growth factor receptor signaling pathway / cell motility / long-term synaptic potentiation / animal organ morphogenesis / RAF activation / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / positive regulation of protein serine/threonine kinase activity / cellular senescence / neuron differentiation / response to peptide hormone / cellular response to xenobiotic stimulus / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / chemotaxis / positive regulation of peptidyl-serine phosphorylation / MAPK cascade / Signaling by BRAF and RAF1 fusions / late endosome / presynapse / heart development / T cell receptor signaling pathway / regulation of cell population proliferation / protein tyrosine kinase activity / cell body / T cell differentiation in thymus / scaffold protein binding / negative regulation of neuron apoptotic process / positive regulation of ERK1 and ERK2 cascade / early endosome / non-specific serine/threonine protein kinase 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) / Beet armyworm (シロイチモジヨトウ) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 4.1 Å | |||||||||
データ登録者 | Park E / Rawson S / Li K / Jeon H / Eck MJ | |||||||||
資金援助 | 米国, 2件
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引用 | ジャーナル: Nature / 年: 2019 タイトル: Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes. 著者: Eunyoung Park / Shaun Rawson / Kunhua Li / Byeong-Won Kim / Scott B Ficarro / Gonzalo Gonzalez-Del Pino / Humayun Sharif / Jarrod A Marto / Hyesung Jeon / Michael J Eck / 要旨: RAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly ...RAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly regulated and inappropriate activation is a frequent cause of cancer; however, the structural basis for RAF regulation is poorly understood at present. Here we use cryo-electron microscopy to determine autoinhibited and active-state structures of full-length BRAF in complexes with MEK1 and a 14-3-3 dimer. The reconstruction reveals an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of two BRAFs, which drives the formation of an active, back-to-back BRAF dimer. Our structural snapshots provide a foundation for understanding normal RAF regulation and its mutational disruption in cancer and developmental syndromes. | |||||||||
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_0541.map.gz | 21.1 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-0541-v30.xml emd-0541.xml | 15.1 KB 15.1 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_0541_fsc.xml | 7.2 KB | 表示 | FSCデータファイル |
画像 | emd_0541.png | 188 KB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-0541 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-0541 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_0541_validation.pdf.gz | 376.8 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_0541_full_validation.pdf.gz | 376.4 KB | 表示 | |
XML形式データ | emd_0541_validation.xml.gz | 9.6 KB | 表示 | |
CIF形式データ | emd_0541_validation.cif.gz | 12.3 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-0541 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-0541 | 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_0541.map.gz / 形式: CCP4 / 大きさ: 30.5 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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注釈 | Structure of a MAPK pathway complex | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.06 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 : Ternary complex of BRAF/MEK1/14-3-3 with MEK inhibitor
全体 | 名称: Ternary complex of BRAF/MEK1/14-3-3 with MEK inhibitor |
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要素 |
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-超分子 #1: Ternary complex of BRAF/MEK1/14-3-3 with MEK inhibitor
超分子 | 名称: Ternary complex of BRAF/MEK1/14-3-3 with MEK inhibitor タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#3 詳細: 14-3-3 is heterodimer of Insect epsilon and zeta. model was generated by Insect zeta sequence as a homo-dimer. |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 実験値: 190 KDa |
-分子 #1: Serine/threonine-protein kinase B-raf
分子 | 名称: Serine/threonine-protein kinase B-raf / 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: 89.402789 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: MSYYHHHHHH HHDIPTTENL YFQGAMDMAA LSGGGGGGAE PGQALFNGDM EPEAGAGAGA AASSAADPAI PEEVWNIKQM IKLTQEHIE ALLDKFGGEH NPPSIYLEAY EEYTSKLDAL QQREQQLLES LGNGTDFSVS SSASMDTVTS SSSSSLSVLP S SLSVFQNP ...文字列: MSYYHHHHHH HHDIPTTENL YFQGAMDMAA LSGGGGGGAE PGQALFNGDM EPEAGAGAGA AASSAADPAI PEEVWNIKQM IKLTQEHIE ALLDKFGGEH NPPSIYLEAY EEYTSKLDAL QQREQQLLES LGNGTDFSVS SSASMDTVTS SSSSSLSVLP S SLSVFQNP TDVARSNPKS PQKPIVRVFL PNKQRTVVPA RCGVTVRDSL KKALMMRGLI PECCAVYRIQ DGEKKPIGWD TD ISWLTGE ELHVEVLENV PLTTHNFVRK TFFTLAFCDF CRKLLFQGFR CQTCGYKFHQ RCSTEVPLMC VNYDQLDLLF VSK FFEHHP IPQEEASLAE TALTSGSSPS APASDSIGPQ ILTSPSPSKS IPIPQPFRPA DEDHRNQFGQ RDRSS(SEP)APNV HINTIEPVN IDDLIRDQGF RGDGGSTTGL SATPPASLPG SLTNVKALQK SPGPQRERKS SSSSEDRNRM KTLGRRDSSD D WEIPDGQI TVGQRIGSGS FGTVYKGKWH GDVAVKMLNV TAPTPQQLQA FKNEVGVLRK TRHVNILLFM GYSTKPQLAI VT QWCEGSS LYHHLHIIET KFEMIKLIDI ARQTAQGMDY LHAKSIIHRD LKSNNIFLHE DLTVKIGDFG LATVKSRWSG SHQ FEQLSG SILWMAPEVI RMQDKNPYSF QSDVYAFGIV LYELMTGQLP YSNINNRDQI IFMVGRGYLS PDLSKVRSNC PKAM KRLMA ECLKKKRDER PLFPQILASI ELLARSLPKI HRSA(SEP)EPSLN RAGFQTEDFS LYACASPKTP IQAGGYGAFP V HGTSAWSH PQFEK |
-分子 #2: Dual specificity mitogen-activated protein kinase kinase 1
分子 | 名称: Dual specificity mitogen-activated protein kinase kinase 1 タイプ: protein_or_peptide / ID: 2 / 詳細: GDC-0623 / コピー数: 1 / 光学異性体: LEVO / EC番号: mitogen-activated protein kinase kinase |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 45.934543 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: MGSSHHHHHH SAVDENLYFQ GGMPKKKPTP IQLNPAPDGS AVNGTSSAET NLEALQKKLE ELELDEQQRK RLEAFLTQKQ KVGELKDDD FEKISELGAG NGGVVFKVSH KPSGLVMARK LIHLEIKPAI RNQIIRELQV LHECNSPYIV GFYGAFYSDG E ISICMEHM ...文字列: MGSSHHHHHH SAVDENLYFQ GGMPKKKPTP IQLNPAPDGS AVNGTSSAET NLEALQKKLE ELELDEQQRK RLEAFLTQKQ KVGELKDDD FEKISELGAG NGGVVFKVSH KPSGLVMARK LIHLEIKPAI RNQIIRELQV LHECNSPYIV GFYGAFYSDG E ISICMEHM DGGSLDQVLK KAGRIPEQIL GKVSIAVIKG LTYLREKHKI MHRDVKPSNI LVNSRGEIKL CDFGVSGQLI DA MANAFVG TRSYMSPERL QGTHYSVQSD IWSMGLSLVE MAVGRYPIPP PDAKELELMF GCQVEGDAAE TPPRPRTPGR PLS SYGMDS RPPMAIFELL DYIVNEPPPK LPSGVFSLEF QDFVNKCLIK NPAERADLKQ LMVHAFIKRS DAEEVDFAGW LCST IGLNQ PSTPTHAAGV |
-分子 #3: 14-3-3 protein zeta
分子 | 名称: 14-3-3 protein zeta / タイプ: protein_or_peptide / ID: 3 / コピー数: 2 / 光学異性体: LEVO |
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由来(天然) | 生物種: Beet armyworm (シロイチモジヨトウ) |
分子量 | 理論値: 28.108514 KDa |
配列 | 文字列: MSVDKEELVQ RAKLAEQAER YDDMAAAMKE VTETGVELSN EERNLLSVAY KNVVGARRSS WRVISSIEQK TEGSERKQQM AKEYRVKVE KELREICYDV LGLLDKHLIP KASNPESKVF YLKMKGDYYR YLAEVATGET RNSVVEDSQK AYQDAFEISK A KMQPTHPI ...文字列: MSVDKEELVQ RAKLAEQAER YDDMAAAMKE VTETGVELSN EERNLLSVAY KNVVGARRSS WRVISSIEQK TEGSERKQQM AKEYRVKVE KELREICYDV LGLLDKHLIP KASNPESKVF YLKMKGDYYR YLAEVATGET RNSVVEDSQK AYQDAFEISK A KMQPTHPI RLGLALNFSV FYYEILNSPD KACQLAKQAF DDAIAELDTL NEDSYKDSTL IMQLLRDNLT LWTSDTQGDG DE PAEGGDN |
-分子 #4: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER
分子 | 名称: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / タイプ: ligand / ID: 4 / コピー数: 1 / 式: AGS |
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分子量 | 理論値: 523.247 Da |
Chemical component information | ChemComp-AGS: |
-分子 #5: ZINC ION
分子 | 名称: ZINC ION / タイプ: ligand / ID: 5 / コピー数: 2 / 式: ZN |
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分子量 | 理論値: 65.409 Da |
-分子 #6: ADENOSINE-5'-DIPHOSPHATE
分子 | 名称: ADENOSINE-5'-DIPHOSPHATE / タイプ: ligand / ID: 6 / コピー数: 1 / 式: ADP |
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分子量 | 理論値: 427.201 Da |
Chemical component information | ChemComp-ADP: |
-分子 #7: MAGNESIUM ION
分子 | 名称: MAGNESIUM ION / タイプ: ligand / ID: 7 / コピー数: 1 / 式: MG |
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分子量 | 理論値: 24.305 Da |
-分子 #8: 5-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)imidazo[1,5-a...
分子 | 名称: 5-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide タイプ: ligand / ID: 8 / コピー数: 1 / 式: LCJ |
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分子量 | 理論値: 456.21 Da |
Chemical component information | ChemComp-LCJ: |
-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
濃度 | 0.05 mg/mL |
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緩衝液 | pH: 7.4 |
グリッド | 詳細: unspecified |
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 K2 SUMMIT (4k x 4k) 平均電子線量: 50.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | C2レンズ絞り径: 70.0 µm / 照射モード: OTHER / 撮影モード: OTHER / Cs: 2.7 mm |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |