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- EMDB-33628: CryoEM structure of PS2-containing gamma-secretase treated with M... -

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Entry
Database: EMDB / ID: EMD-33628
TitleCryoEM structure of PS2-containing gamma-secretase treated with MRK-560
Map dataCryoEM structure of PS2-containing gamma-secretase treated with MRK-560
Sample
  • Complex: PS2-containing gamma-secretase complex treated with MRK-560
    • Protein or peptide: Nicastrin
    • Protein or peptide: Presenilin-2PSEN2
    • Protein or peptide: Gamma-secretase subunit APH-1AGamma secretase
    • Protein or peptide: Gamma-secretase subunit PEN-2Gamma secretase
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CHOLESTEROL
Function / homology
Function and homology information


regulation of calcium import into the mitochondrion / : / amyloid precursor protein biosynthetic process / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of amyloid precursor protein biosynthetic process / Noncanonical activation of NOTCH3 / positive regulation of endopeptidase activity / Notch receptor processing ...regulation of calcium import into the mitochondrion / : / amyloid precursor protein biosynthetic process / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of amyloid precursor protein biosynthetic process / Noncanonical activation of NOTCH3 / positive regulation of endopeptidase activity / Notch receptor processing / central nervous system myelination / membrane protein intracellular domain proteolysis / NOTCH4 Activation and Transmission of Signal to the Nucleus / growth factor receptor binding / Regulated proteolysis of p75NTR / metanephros development / glutamate receptor signaling pathway / amyloid precursor protein metabolic process / regulation of long-term synaptic potentiation / nuclear inner membrane / ciliary rootlet / myeloid cell homeostasis / azurophil granule membrane / dopamine receptor signaling pathway / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / Golgi cisterna membrane / adult behavior / mitochondrion-endoplasmic reticulum membrane tethering / positive regulation of catalytic activity / amyloid precursor protein catabolic process / plasma membrane => GO:0005886 / amyloid-beta formation / membrane protein ectodomain proteolysis / endopeptidase activator activity / EPH-ephrin mediated repulsion of cells / amyloid-beta metabolic process / T cell proliferation / Nuclear signaling by ERBB4 / Notch signaling pathway / NOTCH2 Activation and Transmission of Signal to the Nucleus / cellular response to calcium ion / Degradation of the extracellular matrix / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / cerebellum development / dendritic shaft / epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / sarcolemma / neuromuscular junction / protein processing / kinetochore / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Z disc / calcium ion transport / melanosome / protein-macromolecule adaptor activity / synaptic vesicle / presynaptic membrane / cell cortex / ATPase binding / growth cone / neuron apoptotic process / endopeptidase activity / mitochondrial inner membrane / response to hypoxia / learning or memory / early endosome / endosome membrane / intracellular signal transduction / membrane raft / apical plasma membrane / Amyloid fiber formation / lysosomal membrane / Golgi membrane / focal adhesion / centrosome / neuronal cell body / Neutrophil degranulation / endoplasmic reticulum membrane / negative regulation of apoptotic process / perinuclear region of cytoplasm / Golgi apparatus / enzyme binding / cell surface / endoplasmic reticulum / protein-containing complex / proteolysis / extracellular exosome / membrane / nucleus / plasma membrane
Similarity search - Function
Peptidase A22A, presenilin 2 / 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 2 / 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 / Nicastrin small lobe / Presenilin/signal peptide peptidase / Presenilin, signal peptide peptidase, family
Similarity search - Domain/homology
Presenilin-2 / 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
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 Natural Science Foundation of China (NSFC)81920108015 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-
UpdateNov 2, 2022-
Current statusNov 2, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33628.png

Downloads & links

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Map

FileDownload / File: emd_33628.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM structure of PS2-containing gamma-secretase treated with MRK-560
Voxel sizeX=Y=Z: 1.0825 Å
Density
Contour LevelBy AUTHOR: 0.0276
Minimum - Maximum-0.10412303 - 0.16528285
Average (Standard dev.)0.0010516417 (±0.0057144132)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 216.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33628_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_33628_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : PS2-containing gamma-secretase complex treated with MRK-560

EntireName: PS2-containing gamma-secretase complex treated with MRK-560
Components
  • Complex: PS2-containing gamma-secretase complex treated with MRK-560
    • Protein or peptide: Nicastrin
    • Protein or peptide: Presenilin-2PSEN2
    • Protein or peptide: Gamma-secretase subunit APH-1AGamma secretase
    • Protein or peptide: Gamma-secretase subunit PEN-2Gamma secretase
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CHOLESTEROL

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Supramolecule #1: PS2-containing gamma-secretase complex treated with MRK-560

SupramoleculeName: PS2-containing gamma-secretase complex treated with MRK-560
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: 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

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Macromolecule #2: Presenilin-2

MacromoleculeName: Presenilin-2 / 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: 50.172035 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MLTFMASDSE EEVCDERTSL MSAESPTPRS CQEGRQGPED GENTAQWRSQ ENEEDGEEDP DRYVCSGVPG RPPGLEEELT LKYGAKHVI MLFVPVTLCM IVVVATIKSV RFYTEKNGQL IYTPFTEDTP SVGQRLLNSV LNTLIMISVI VVMTIFLVVL Y KYRCYKFI ...String:
MLTFMASDSE EEVCDERTSL MSAESPTPRS CQEGRQGPED GENTAQWRSQ ENEEDGEEDP DRYVCSGVPG RPPGLEEELT LKYGAKHVI MLFVPVTLCM IVVVATIKSV RFYTEKNGQL IYTPFTEDTP SVGQRLLNSV LNTLIMISVI VVMTIFLVVL Y KYRCYKFI HGWLIMSSLM LLFLFTYIYL GEVLKTYNVA MDYPTLLLTV WNFGAVGMVC IHWKGPLVLQ QAYLIMISAL MA LVFIKYL PEWSAWVILG AISVYDLVAV LCPKGPLRML VETAQERNEP IFPALIYSSA MVWTVGMAKL DPSSQGALQL PYD PEMEED SYDSFGEPSY PEVFEPPLTG YPGEELEEEE ERGVKLGLGD FIFYSVLVGK AAATGSGDWN TTLACFVAIL IGLC LTLLL LAVFKKALPA LPISITFGLI FYFSTDNLVR PFMDTLASHQ LYI

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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

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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

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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 / N-Acetylglucosamine

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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 / Phosphatidylcholine

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Macromolecule #9: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 9 / Number of copies: 3 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / 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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

0957

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 200955

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