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- EMDB-33624: CryoEM structure of PS1-containing gamma-secretase in complex wit... -

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Entry
Database: EMDB / ID: EMD-33624
TitleCryoEM structure of PS1-containing gamma-secretase in complex with MRK-560
Map dataCryoEM structure of human PS1-containing gamma-secretase in complex with MRK-560
Sample
  • Complex: PS1-containing gamma-secretase in complex with MRK-560
    • 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: ~{N}-[4-[2,5-bis(fluoranyl)phenyl]-4-(4-chlorophenyl)sulfonyl-cyclohexyl]-1,1,1-tris(fluoranyl)methanesulfonamide
  • Ligand: CHOLESTEROL
KeywordsIntramembrane protease / gamma-secretase / presenilin-1 / MEMBRANE PROTEIN / MEMBRANE PROTEIN-HYDROLASE complex
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: 2.9 Å
AuthorsGuo X / Wang Y / Zhou J / Jin C / Wang J / Jia B / Jing D / Yan C / Lei J / Zhou R / Shi Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Basic Research Program of China (973 Program)2020YFA0509300 China
CitationJournal: Nat Commun / Year: 2022
Title: Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560.
Authors: Xuefei Guo / Yumeng Wang / Jiayao Zhou / Chen Jin / Jiaoni Wang / Bojun Jia / Dan Jing / Chuangye Yan / Jianlin Lei / Rui Zhou / Yigong Shi /
Abstract: Inhibition of γ-secretase activity represents a potential therapeutic strategy for Alzheimer's disease (AD). MRK-560 is a selective inhibitor with higher potency for Presenilin 1 (PS1) than for PS2, ...Inhibition of γ-secretase activity represents a potential therapeutic strategy for Alzheimer's disease (AD). MRK-560 is a selective inhibitor with higher potency for Presenilin 1 (PS1) than for PS2, the two isoforms of the catalytic subunit of γ-secretase, although the underlying mechanism remains elusive. Here we report the cryo-electron microscopy (cryo-EM) structures of PS1 and PS2-containing γ-secretase complexes with and without MRK-560 at overall resolutions of 2.9-3.4 Å. MRK-560 occupies the substrate binding site of PS1, but is invisible in PS2. Structural comparison identifies Thr281 and Leu282 in PS1 to be the determinant for isoform-dependent sensitivity to MRK-560, which is confirmed by swapping experiment between PS1 and PS2. By revealing the mechanism for isoform-selective inhibition of presenilin, our work may facilitate future drug discovery targeting γ-secretase.
History
DepositionJun 17, 2022-
Header (metadata) releaseNov 2, 2022-
Map releaseNov 2, 2022-
UpdateJun 18, 2025-
Current statusJun 18, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33624.png

Downloads & links

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Map

FileDownload / File: emd_33624.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM structure of human PS1-containing gamma-secretase in complex with MRK-560
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 320 pix.
= 346.4 Å		1.08 Å/pix.
x 320 pix.
= 346.4 Å		1.08 Å/pix.
x 320 pix.
= 346.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.021
Minimum - Maximum-0.043680444 - 0.101466075
Average (Standard dev.)0.0000509561 (±0.0027581505)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 346.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33624_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_33624_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : PS1-containing gamma-secretase in complex with MRK-560

EntireName: PS1-containing gamma-secretase in complex with MRK-560
Components
  • Complex: PS1-containing gamma-secretase in complex with MRK-560
    • 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: ~{N}-[4-[2,5-bis(fluoranyl)phenyl]-4-(4-chlorophenyl)sulfonyl-cyclohexyl]-1,1,1-tris(fluoranyl)methanesulfonamide
  • Ligand: CHOLESTEROL

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Supramolecule #1: PS1-containing gamma-secretase in complex with MRK-560

SupramoleculeName: PS1-containing gamma-secretase in complex with MRK-560
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: 12.038029 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MNLERVSNEE KLNLCRKYYL GGFAFLPFLW LVNIFWFFRE AFLVPAYTEQ SQIKGYVWRS AVGFLFWVIV LTSWITIFQI YRPRWGALG DYLSFTIPLG TP

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: ~{N}-[4-[2,5-bis(fluoranyl)phenyl]-4-(4-chlorophenyl)sulfonyl-cyc...

MacromoleculeName: ~{N}-[4-[2,5-bis(fluoranyl)phenyl]-4-(4-chlorophenyl)sulfonyl-cyclohexyl]-1,1,1-tris(fluoranyl)methanesulfonamide
type: ligand / ID: 9 / Number of copies: 1 / Formula: IGD
Molecular weightTheoretical: 517.918 Da
Chemical component information

ChemComp-IGD:
~{N}-[4-[2,5-bis(fluoranyl)phenyl]-4-(4-chlorophenyl)sulfonyl-cyclohexyl]-1,1,1-tris(fluoranyl)methanesulfonamide

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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 K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: EMDB MAP
EMDB ID:

0957

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 127676
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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