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- EMDB-0957: Molecular basis for inhibition of human gamma-secretase by small ... -

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Basic information

Entry
Database: EMDB / ID: EMD-0957
TitleMolecular basis for inhibition of human gamma-secretase by small molecule
Map data
Sample
  • Complex: human gamma-secretase
    • Protein or peptide: Nicastrin
    • Protein or peptide: Presenilin-1
    • Protein or peptide: Gamma-secretase subunit APH-1A
    • Protein or peptide: Gamma-secretase subunit PEN-2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: (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
  • Ligand: CHOLESTEROL
KeywordsInhibitor / MEMBRANE PROTEIN
Function / homology
Function and homology information


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 endopeptidase activity / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of amyloid precursor protein biosynthetic process / Noncanonical activation of NOTCH3 ...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 endopeptidase activity / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of amyloid precursor protein biosynthetic process / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse / TGFBR3 PTM regulation / sequestering of calcium ion / Notch receptor processing / synaptic vesicle targeting / positive regulation of coagulation / negative regulation of axonogenesis / central nervous system myelination / membrane protein intracellular domain proteolysis / growth factor receptor binding / T cell activation involved in immune response / skin morphogenesis / choline transport / NOTCH4 Activation and Transmission of Signal to the Nucleus / dorsal/ventral neural tube patterning / neural retina development / regulation of resting membrane potential / myeloid dendritic cell differentiation / L-glutamate import across plasma membrane / Regulated proteolysis of p75NTR / regulation of phosphorylation / metanephros development / locomotion / brain morphogenesis / endoplasmic reticulum calcium ion homeostasis / nuclear outer membrane / amyloid precursor protein metabolic process / regulation of synaptic vesicle cycle / regulation of long-term synaptic potentiation / smooth endoplasmic reticulum calcium ion homeostasis / embryonic limb morphogenesis / regulation of postsynapse organization / astrocyte activation involved in immune response / cell fate specification / regulation of canonical Wnt signaling pathway / skeletal system morphogenesis / aggresome / myeloid cell homeostasis / azurophil granule membrane / G protein-coupled dopamine receptor signaling pathway / glutamate receptor signaling pathway / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / ciliary rootlet / Golgi cisterna membrane / positive regulation of dendritic spine development / positive regulation of amyloid fibril formation / positive regulation of receptor recycling / regulation of neuron projection development / protein glycosylation / blood vessel development / mitochondrial transport / amyloid precursor protein catabolic process / adult behavior / heart looping / cerebral cortex cell migration / amyloid-beta formation / membrane protein ectodomain proteolysis / negative regulation of apoptotic signaling pathway / autophagosome assembly / EPH-ephrin mediated repulsion of cells / negative regulation of ubiquitin-dependent protein catabolic process / endopeptidase activator activity / neuron development / somitogenesis / smooth endoplasmic reticulum / hematopoietic progenitor cell differentiation / Nuclear signaling by ERBB4 / calcium ion homeostasis / T cell proliferation / regulation of synaptic transmission, glutamatergic / rough endoplasmic reticulum / Notch signaling pathway / Degradation of the extracellular matrix / neuron projection maintenance / NOTCH2 Activation and Transmission of Signal to the Nucleus / cerebellum development / cellular response to calcium ion / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / dendritic shaft / thymus development / positive regulation of glycolytic process / epithelial cell proliferation / post-embryonic development / PDZ domain binding / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / apoptotic signaling pathway / synapse organization / neuromuscular junction
Similarity search - Function
Peptidase A22A, presenilin 1 / Gamma-secretase subunit Aph-1 / Gamma-secretase aspartyl protease complex, presenilin enhancer-2 subunit / Aph-1 protein / Presenilin enhancer-2 subunit of gamma secretase / Peptidase A22A, presenilin / Presenilin, C-terminal / Presenilin / Nicastrin / Nicastrin, small lobe ...Peptidase A22A, presenilin 1 / Gamma-secretase subunit Aph-1 / Gamma-secretase aspartyl protease complex, presenilin enhancer-2 subunit / Aph-1 protein / Presenilin enhancer-2 subunit of gamma secretase / Peptidase A22A, presenilin / Presenilin, C-terminal / Presenilin / Nicastrin / Nicastrin, small lobe / Nicastrin large lobe / Nicastrin small lobe / Presenilin/signal peptide peptidase / Presenilin, signal peptide peptidase, family
Similarity search - Domain/homology
Presenilin-1 / Nicastrin / Gamma-secretase subunit APH-1A / Gamma-secretase subunit PEN-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsYang G / Zhou R
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81920108015 China
CitationJournal: 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
DepositionJan 15, 2020-
Header (metadata) releaseJan 27, 2021-
Map releaseJan 27, 2021-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.035
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.035
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6lr4
  • Surface level: 0.035
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0957.png

Downloads & links

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Map

FileDownload / File: emd_0957.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 320 pix.
= 349.12 Å		1.09 Å/pix.
x 320 pix.
= 349.12 Å		1.09 Å/pix.
x 320 pix.
= 349.12 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.091 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.028 / Movie #1: 0.035
Minimum - Maximum-0.08830598 - 0.16979113
Average (Standard dev.)-0.000031530104 (±0.003939962)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 349.12 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0911.0911.091
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z349.120349.120349.120
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.0880.170-0.000

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Supplemental data

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Sample components

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Entire : human gamma-secretase

EntireName: human gamma-secretase
Components
  • Complex: human gamma-secretase
    • Protein or peptide: Nicastrin
    • Protein or peptide: Presenilin-1
    • Protein or peptide: Gamma-secretase subunit APH-1A
    • Protein or peptide: Gamma-secretase subunit PEN-2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: (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
  • Ligand: CHOLESTEROL

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Supramolecule #1: human gamma-secretase

SupramoleculeName: human gamma-secretase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Nicastrin

MacromoleculeName: Nicastrin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 78.48357 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

UniProtKB: Nicastrin

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Macromolecule #2: Presenilin-1

MacromoleculeName: Presenilin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.713535 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

UniProtKB: Presenilin-1

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Macromolecule #3: Gamma-secretase subunit APH-1A

MacromoleculeName: Gamma-secretase subunit APH-1A / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 29.017943 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

UniProtKB: Gamma-secretase subunit APH-1A

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Macromolecule #4: Gamma-secretase subunit PEN-2

MacromoleculeName: Gamma-secretase subunit PEN-2 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.49868 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTNLERVSN EEKLNLCRKY YLGGFAFLPF LWLVNIFWFF REAFLVPAY TEQSQIKGYV WRSAVGFLFW VIVLTSWITI FQIYRPRWGA LGDYLSFTIP LGTP

UniProtKB: Gamma-secretase subunit PEN-2

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #8: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 8 / Number of copies: 2 / Formula: PC1
Molecular weightTheoretical: 790.145 Da
Chemical component information

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

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Macromolecule #9: (2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihyd...

MacromoleculeName: (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
Molecular weightTheoretical: 361.435 Da
Chemical component information

ChemComp-ESF:
(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

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Macromolecule #10: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 10 / Number of copies: 3 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 1.5625 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1044389
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: MAXIMUM LIKELIHOOD

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