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Yorodumi- EMDB-0957: Molecular basis for inhibition of human gamma-secretase by small ... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-0957 | |||||||||
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Title | Molecular basis for inhibition of human gamma-secretase by small molecule | |||||||||
Map data | ||||||||||
Sample |
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Function / homology | Function and homology information Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / positive regulation of coagulation / negative regulation of core promoter binding / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / protein catabolic process at postsynapse / 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 / positive regulation of coagulation / negative regulation of core promoter binding / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / protein catabolic process at postsynapse / positive regulation of amyloid precursor protein biosynthetic process / positive regulation of endopeptidase activity / TGFBR3 PTM regulation / Noncanonical activation of NOTCH3 / 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 / myeloid dendritic cell differentiation / neural retina development / L-glutamate import across plasma membrane / Regulated proteolysis of p75NTR / regulation of phosphorylation / metanephros development / endoplasmic reticulum calcium ion homeostasis / locomotion / brain morphogenesis / nuclear outer membrane / amyloid precursor protein metabolic process / glutamate receptor signaling pathway / smooth endoplasmic reticulum calcium ion homeostasis / regulation of canonical Wnt signaling pathway / astrocyte activation involved in immune response / regulation of long-term synaptic potentiation / embryonic limb morphogenesis / aggresome / cell fate specification / skeletal system morphogenesis / ciliary rootlet / myeloid cell homeostasis / azurophil granule membrane / regulation of postsynapse organization / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / G protein-coupled dopamine receptor signaling pathway / Golgi cisterna membrane / positive regulation of amyloid fibril formation / mitochondrial transport / adult behavior / positive regulation of dendritic spine development / positive regulation of receptor recycling / blood vessel development / regulation of neuron projection development / heart looping / protein glycosylation / amyloid precursor protein catabolic process / cerebral cortex cell migration / amyloid-beta formation / negative regulation of apoptotic signaling pathway / membrane protein ectodomain proteolysis / autophagosome assembly / endopeptidase activator activity / EPH-ephrin mediated repulsion of cells / smooth endoplasmic reticulum / hematopoietic progenitor cell differentiation / neuron development / somitogenesis / negative regulation of ubiquitin-dependent protein catabolic process / calcium ion homeostasis / T cell proliferation / Nuclear signaling by ERBB4 / rough endoplasmic reticulum / Notch signaling pathway / regulation of synaptic transmission, glutamatergic / neuron projection maintenance / Degradation of the extracellular matrix / NOTCH2 Activation and Transmission of Signal to the Nucleus / cellular response to calcium ion / positive regulation of glycolytic process / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / cerebellum development / post-embryonic development / epithelial cell proliferation / thymus development / negative regulation of protein phosphorylation / dendritic shaft / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / PDZ domain binding / apoptotic signaling pathway / synapse organization Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.0 Å | |||||||||
Authors | Yang G / Zhou R / Guo X / Lei J / Shi Y | |||||||||
Funding support | China, 1 items
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Citation | Journal: Cell / Year: 2021 Title: Structural basis of γ-secretase inhibition and modulation by small molecule drugs. Authors: Guanghui Yang / Rui Zhou / Xuefei Guo / Chuangye Yan / Jianlin Lei / Yigong Shi / Abstract: 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. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_0957.map.gz | 116.8 MB | EMDB map data format | |
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Header (meta data) | emd-0957-v30.xml emd-0957.xml | 15 KB 15 KB | Display Display | EMDB header |
Images | emd_0957.png | 145.7 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-0957 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-0957 | HTTPS FTP |
-Validation report
Summary document | emd_0957_validation.pdf.gz | 494.7 KB | Display | EMDB validaton report |
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Full document | emd_0957_full_validation.pdf.gz | 494.3 KB | Display | |
Data in XML | emd_0957_validation.xml.gz | 6.5 KB | Display | |
Data in CIF | emd_0957_validation.cif.gz | 7.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-0957 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-0957 | HTTPS FTP |
-Related structure data
Related structure data | 6lr4MC 0944C 6lqgC 7c9iC 7d8xC C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_0957.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.091 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : human gamma-secretase
Entire | Name: human gamma-secretase |
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Components |
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-Supramolecule #1: human gamma-secretase
Supramolecule | Name: human gamma-secretase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
-Macromolecule #1: Nicastrin
Macromolecule | Name: Nicastrin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 78.48357 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MATAGGGSGA DPGSRGLLRL LSFCVLLAGL CRGNSVERKI YIPLNKTAPC VRLLNATHQI GCQSSISGDT GVIHVVEKEE DLQWVLTDG PNPPYMVLLE SKHFTRDLME KLKGRTSRIA GLAVSLTKPS PASGFSPSVQ CPNDGFGVYS NSYGPEFAHC R EIQWNSLG ...String: 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 |
-Macromolecule #2: Presenilin-1
Macromolecule | Name: Presenilin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO EC number: Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 52.713535 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPV TLCMVVVVAT IKSVSFYTRK DGQLIYTPFT EDTETVGQRA LHSILNAAIM ISVIVVMTIL LVVLYKYRCY K VIHAWLII ...String: 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 |
-Macromolecule #3: Gamma-secretase subunit APH-1A
Macromolecule | Name: Gamma-secretase subunit APH-1A / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 29.017943 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MGAAVFFGCT FVAFGPAFAL FLITVAGDPL RVIILVAGAF FWLVSLLLAS VVWFILVHVT DRSDARLQYG LLIFGAAVSV LLQEVFRFA YYKLLKKADE GLASLSEDGR SPISIRQMAY VSGLSFGIIS GVFSVINILA DALGPGVVGI HGDSPYYFLT S AFLTAAII ...String: 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 |
-Macromolecule #4: Gamma-secretase subunit PEN-2
Macromolecule | Name: Gamma-secretase subunit PEN-2 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 16.49868 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTNLERVSN EEKLNLCRKY YLGGFAFLPF LWLVNIFWFF REAFLVPAY TEQSQIKGYV WRSAVGFLFW VIVLTSWITI FQIYRPRWGA LGDYLSFTIP LGTP |
-Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 6 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #8: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
Macromolecule | Name: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 8 / Number of copies: 2 / Formula: PC1 |
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Molecular weight | Theoretical: 790.145 Da |
Chemical component information | ChemComp-PC1: |
-Macromolecule #9: (2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihyd...
Macromolecule | Name: (2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide type: ligand / ID: 9 / Number of copies: 1 / Formula: ESF |
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Molecular weight | Theoretical: 361.435 Da |
Chemical component information | ChemComp-ESF: |
-Macromolecule #10: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 10 / Number of copies: 3 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ChemComp-CLR: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 1.5625 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1044389 |
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Initial angle assignment | Type: PROJECTION MATCHING |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |