+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-30312 | |||||||||
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タイトル | Human gamma-secretase in complex with small molecule L-685,458 | |||||||||
マップデータ | gamma-secretase in complex with a small molecule | |||||||||
試料 |
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機能・相同性 | 機能・相同性情報 Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / positive regulation of coagulation / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of endopeptidase activity / positive regulation of amyloid precursor protein biosynthetic process ...Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / positive regulation of coagulation / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of endopeptidase activity / positive regulation of amyloid precursor protein biosynthetic process / protein catabolic process at postsynapse / Noncanonical activation of NOTCH3 / TGFBR3 PTM regulation / sequestering of calcium ion / Notch receptor processing / central nervous system myelination / synaptic vesicle targeting / negative regulation of axonogenesis / membrane protein intracellular domain proteolysis / regulation of resting membrane potential / choline transport / T cell activation involved in immune response / skin morphogenesis / NOTCH4 Activation and Transmission of Signal to the Nucleus / growth factor receptor binding / regulation of synaptic vesicle cycle / dorsal/ventral neural tube patterning / neural retina development / myeloid dendritic cell differentiation / L-glutamate import across plasma membrane / Regulated proteolysis of p75NTR / endoplasmic reticulum calcium ion homeostasis / metanephros development / regulation of phosphorylation / locomotion / brain morphogenesis / nuclear outer membrane / amyloid precursor protein metabolic process / skeletal system morphogenesis / myeloid cell homeostasis / smooth endoplasmic reticulum calcium ion homeostasis / regulation of long-term synaptic potentiation / astrocyte activation involved in immune response / regulation of canonical Wnt signaling pathway / embryonic limb morphogenesis / aggresome / cell fate specification / glutamate receptor signaling pathway / ciliary rootlet / azurophil granule membrane / regulation of postsynapse organization / G protein-coupled dopamine receptor signaling pathway / Golgi cisterna membrane / positive regulation of amyloid fibril formation / mitochondrial transport / 加水分解酵素; プロテアーゼ; ペプチド結合加水分解酵素; アスパラギン酸プロテアーゼ / positive regulation of dendritic spine development / positive regulation of receptor recycling / adult behavior / blood vessel development / regulation of neuron projection development / heart looping / amyloid precursor protein catabolic process / cerebral cortex cell migration / protein glycosylation / amyloid-beta formation / negative regulation of apoptotic signaling pathway / membrane protein ectodomain proteolysis / autophagosome assembly / endopeptidase activator activity / EPH-ephrin mediated repulsion of cells / neuron development / somitogenesis / smooth endoplasmic reticulum / hematopoietic progenitor cell differentiation / negative regulation of ubiquitin-dependent protein catabolic process / calcium ion homeostasis / Nuclear signaling by ERBB4 / T cell proliferation / rough endoplasmic reticulum / regulation of synaptic transmission, glutamatergic / Notch signaling pathway / neuron projection maintenance / NOTCH2 Activation and Transmission of Signal to the Nucleus / Degradation of the extracellular matrix / post-embryonic development / positive regulation of glycolytic process / NRIF signals cell death from the nucleus / cellular response to calcium ion / Activated NOTCH1 Transmits Signal to the Nucleus / negative regulation of protein phosphorylation / cerebellum development / thymus development / epithelial cell proliferation / dendritic shaft / apoptotic signaling pathway / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / PDZ domain binding / neuron migration 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: 3.1 Å | |||||||||
データ登録者 | Yang G / Zhou R / Guo X / Lei J / Yan C / Shi Y | |||||||||
資金援助 | 中国, 1件
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引用 | ジャーナル: Cell / 年: 2021 タイトル: Structural basis of γ-secretase inhibition and modulation by small molecule drugs. 著者: Guanghui Yang / Rui Zhou / Xuefei Guo / Chuangye Yan / Jianlin Lei / Yigong Shi / 要旨: Development of γ-secretase inhibitors (GSIs) and modulators (GSMs) represents an attractive therapeutic opportunity for Alzheimer's disease (AD) and cancers. However, how these GSIs and GSMs target ...Development of γ-secretase inhibitors (GSIs) and modulators (GSMs) represents an attractive therapeutic opportunity for Alzheimer's disease (AD) and cancers. However, how these GSIs and GSMs target γ-secretase has remained largely unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human γ-secretase bound individually to two GSI clinical candidates, Semagacestat and Avagacestat, a transition state analog GSI L685,458, and a classic GSM E2012, at overall resolutions of 2.6-3.1 Å. Remarkably, each of the GSIs occupies the same general location on presenilin 1 (PS1) that accommodates the β strand from amyloid precursor protein or Notch, interfering with substrate recruitment. L685,458 directly coordinates the two catalytic aspartate residues of PS1. E2012 binds to an allosteric site of γ-secretase on the extracellular side, potentially explaining its modulating activity. Structural analysis reveals a set of shared themes and variations for inhibitor and modulator recognition that will guide development of the next-generation substrate-selective inhibitors. | |||||||||
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_30312.map.gz | 116.7 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-30312-v30.xml emd-30312.xml | 14.9 KB 14.9 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_30312.png | 88.8 KB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-30312 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-30312 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_30312_validation.pdf.gz | 462.2 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_30312_full_validation.pdf.gz | 461.7 KB | 表示 | |
XML形式データ | emd_30312_validation.xml.gz | 6.4 KB | 表示 | |
CIF形式データ | emd_30312_validation.cif.gz | 7.3 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-30312 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-30312 | 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_30312.map.gz / 形式: CCP4 / 大きさ: 125 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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注釈 | gamma-secretase in complex with a small molecule | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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: 1.091 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 : human gamma-secretase
全体 | 名称: human gamma-secretase |
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要素 |
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-超分子 #1: human gamma-secretase
超分子 | 名称: human gamma-secretase / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#4 |
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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 #1: Nicastrin
分子 | 名称: Nicastrin / 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: 78.48357 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: MATAGGGSGA DPGSRGLLRL LSFCVLLAGL CRGNSVERKI YIPLNKTAPC VRLLNATHQI GCQSSISGDT GVIHVVEKEE DLQWVLTDG PNPPYMVLLE SKHFTRDLME KLKGRTSRIA GLAVSLTKPS PASGFSPSVQ CPNDGFGVYS NSYGPEFAHC R EIQWNSLG ...文字列: MATAGGGSGA DPGSRGLLRL LSFCVLLAGL CRGNSVERKI YIPLNKTAPC VRLLNATHQI GCQSSISGDT GVIHVVEKEE DLQWVLTDG PNPPYMVLLE SKHFTRDLME KLKGRTSRIA GLAVSLTKPS PASGFSPSVQ CPNDGFGVYS NSYGPEFAHC R EIQWNSLG NGLAYEDFSF PIFLLEDENE TKVIKQCYQD HNLSQNGSAP TFPLCAMQLF SHMHAVISTA TCMRRSSIQS TF SINPEIV CDPLSDYNVW SMLKPINTTG TLKPDDRVVV AATRLDSRSF FWNVAPGAES AVASFVTQLA AAEALQKAPD VTT LPRNVM FVFFQGETFD YIGSSRMVYD MEKGKFPVQL ENVDSFVELG QVALRTSLEL WMHTDPVSQK NESVRNQVED LLAT LEKSG AGVPAVILRR PNQSQPLPPS SLQRFLRARN ISGVVLADHS GAFHNKYYQS IYDTAENINV SYPEWLSPEE DLNFV TDTA KALADVATVL GRALYELAGG TNFSDTVQAD PQTVTRLLYG FLIKANNSWF QSILRQDLRS YLGDGPLQHY IAVSSP TNT TYVVQYALAN LTGTVVNLTR EQCQDPSKVP SENKDLYEYS WVQGPLHSNE TDRLPRCVRS TARLARALSP AFELSQW SS TEYSTWTESR WKDIRARIFL IASKELELIT LTVGFGILIF SLIVTYCINA KADVLFIAPR EPGAVSY |
-分子 #2: Presenilin-1
分子 | 名称: Presenilin-1 / タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO EC番号: 加水分解酵素; プロテアーゼ; ペプチド結合加水分解酵素; アスパラギン酸プロテアーゼ |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 52.713535 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPV TLCMVVVVAT IKSVSFYTRK DGQLIYTPFT EDTETVGQRA LHSILNAAIM ISVIVVMTIL LVVLYKYRCY K VIHAWLII ...文字列: MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPV TLCMVVVVAT IKSVSFYTRK DGQLIYTPFT EDTETVGQRA LHSILNAAIM ISVIVVMTIL LVVLYKYRCY K VIHAWLII SSLLLLFFFS FIYLGEVFKT YNVAVDYITV ALLIWNFGVV GMISIHWKGP LRLQQAYLIM ISALMALVFI KY LPEWTAW LILAVISVYD LVAVLCPKGP LRMLVETAQE RNETLFPALI YSSTMVWLVN MAEGDPEAQR RVSKNSKYNA EST ERESQD TVAENDDGGF SEEWEAQRDS HLGPHRSTPE SRAAVQELSS SILAGEDPEE RGVKLGLGDF IFYSVLVGKA SATA SGDWN TTIACFVAIL IGLCLTLLLL AIFKKALPAL PISITFGLVF YFATDYLVQP FMDQLAFHQF YI |
-分子 #3: Gamma-secretase subunit APH-1A
分子 | 名称: Gamma-secretase subunit APH-1A / タイプ: protein_or_peptide / ID: 3 / 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: 29.017943 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: MGAAVFFGCT FVAFGPAFAL FLITVAGDPL RVIILVAGAF FWLVSLLLAS VVWFILVHVT DRSDARLQYG LLIFGAAVSV LLQEVFRFA YYKLLKKADE GLASLSEDGR SPISIRQMAY VSGLSFGIIS GVFSVINILA DALGPGVVGI HGDSPYYFLT S AFLTAAII ...文字列: MGAAVFFGCT FVAFGPAFAL FLITVAGDPL RVIILVAGAF FWLVSLLLAS VVWFILVHVT DRSDARLQYG LLIFGAAVSV LLQEVFRFA YYKLLKKADE GLASLSEDGR SPISIRQMAY VSGLSFGIIS GVFSVINILA DALGPGVVGI HGDSPYYFLT S AFLTAAII LLHTFWGVVF FDACERRRYW ALGLVVGSHL LTSGLTFLNP WYEASLLPIY AVTVSMGLWA FITAGGSLRS IQ RSLLCRR QEDSRVMVYS ALRIPPED |
-分子 #4: Gamma-secretase subunit PEN-2
分子 | 名称: Gamma-secretase subunit PEN-2 / タイプ: protein_or_peptide / ID: 4 / 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: 16.49868 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTNLERVSN EEKLNLCRKY YLGGFAFLPF LWLVNIFWFF REAFLVPAY TEQSQIKGYV WRSAVGFLFW VIVLTSWITI FQIYRPRWGA LGDYLSFTIP LGTP |
-分子 #7: 2-acetamido-2-deoxy-beta-D-glucopyranose
分子 | 名称: 2-acetamido-2-deoxy-beta-D-glucopyranose / タイプ: ligand / ID: 7 / コピー数: 6 / 式: NAG |
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分子量 | 理論値: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-分子 #8: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
分子 | 名称: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / タイプ: ligand / ID: 8 / コピー数: 2 / 式: PC1 |
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分子量 | 理論値: 790.145 Da |
Chemical component information | ChemComp-PC1: |
-分子 #9: ~{tert}-butyl ~{N}-[(2~{S},3~{R},5~{R})-6-[[(2~{S})-1-[[(2~{S})-1...
分子 | 名称: ~{tert}-butyl ~{N}-[(2~{S},3~{R},5~{R})-6-[[(2~{S})-1-[[(2~{S})-1-azanyl-1-oxidanylidene-3-phenyl-propan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]amino]-3-oxidanyl-6-oxidanylidene-1- ...名称: ~{tert}-butyl ~{N}-[(2~{S},3~{R},5~{R})-6-[[(2~{S})-1-[[(2~{S})-1-azanyl-1-oxidanylidene-3-phenyl-propan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]amino]-3-oxidanyl-6-oxidanylidene-1-phenyl-5-(phenylmethyl)hexan-2-yl]carbamate タイプ: ligand / ID: 9 / コピー数: 1 / 式: FTO |
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分子量 | 理論値: 672.853 Da |
Chemical component information | ChemComp-FTO: |
-分子 #10: CHOLESTEROL
分子 | 名称: CHOLESTEROL / タイプ: ligand / ID: 10 / コピー数: 3 / 式: CLR |
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分子量 | 理論値: 386.654 Da |
Chemical component information | ChemComp-CLR: |
-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 K2 SUMMIT (4k x 4k) 平均電子線量: 1.5625 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: 3.1 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 320661 |
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初期 角度割当 | タイプ: PROJECTION MATCHING |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |