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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


positive regulation of endopeptidase activity / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse / TGFBR3 PTM regulation / Notch receptor processing / skin morphogenesis / membrane protein intracellular domain proteolysis / NOTCH4 Activation and Transmission of Signal to the Nucleus ...positive regulation of endopeptidase activity / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse / TGFBR3 PTM regulation / Notch receptor processing / skin morphogenesis / membrane protein intracellular domain proteolysis / NOTCH4 Activation and Transmission of Signal to the Nucleus / ciliary rootlet / neural retina development / Regulated proteolysis of p75NTR / mitochondria-associated endoplasmic reticulum membrane contact site / aggresome / amyloid precursor protein metabolic process / endoplasmic reticulum calcium ion homeostasis / regulation of synaptic vesicle cycle / regulation of postsynapse organization / astrocyte activation involved in immune response / regulation of neuron projection development / regulation of canonical Wnt signaling pathway / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / Golgi cisterna membrane / growth factor receptor binding / azurophil granule membrane / positive regulation of amyloid fibril formation / positive regulation of dendritic spine development / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / smooth endoplasmic reticulum / positive regulation of receptor recycling / nuclear outer membrane / EPH-ephrin mediated repulsion of cells / cerebellum development / Notch signaling pathway / negative regulation of ubiquitin-dependent protein catabolic process / Nuclear signaling by ERBB4 / endopeptidase activator activity / calcium ion homeostasis / Degradation of the extracellular matrix / rough endoplasmic reticulum / neuron projection maintenance / astrocyte activation / positive regulation of glycolytic process / NOTCH2 Activation and Transmission of Signal to the Nucleus / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / dendritic shaft / protein processing / PDZ domain binding / neuromuscular junction / cell-cell adhesion / NOTCH3 Activation and Transmission of Signal to the Nucleus / memory / sarcolemma / synapse organization / beta-catenin binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / cellular response to amyloid-beta / kinetochore / calcium channel activity / positive regulation of tumor necrosis factor production / melanosome / regulation of gene expression / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / negative regulation of neuron apoptotic process / synaptic vesicle / nuclear membrane / ATPase binding / growth cone / presynaptic membrane / early endosome membrane / endopeptidase activity / cell cortex / aspartic-type endopeptidase activity / molecular adaptor activity / early endosome / learning or memory / protein-macromolecule adaptor activity / postsynapse / endosome membrane / neuron projection / intracellular signal transduction / mitochondrial inner membrane / cadherin binding / membrane raft / Amyloid fiber formation / negative regulation of gene expression / Golgi membrane / focal adhesion / lysosomal membrane / apoptotic process / centrosome / neuronal cell body / positive regulation of gene expression / negative regulation of apoptotic process / Neutrophil degranulation
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-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing 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

CTF correctionType: NONE
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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