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- PDB-8kcs: Cryo-EM structure of human gamma-secretase in complex with BMS906024 -

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Basic information

Entry
Database: PDB / ID: 8kcs
TitleCryo-EM structure of human gamma-secretase in complex with BMS906024
Components
  • (Gamma-secretase subunit ...) x 2
  • Nicastrin
  • Presenilin-1
KeywordsMEMBRANE PROTEIN / Intramembrane protease / gamma-secretase / gamma-secretase inhibitor / 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 coagulation / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of endopeptidase activity / 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 / negative regulation of core promoter binding / positive regulation of coagulation / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of endopeptidase activity / positive regulation of amyloid precursor protein biosynthetic process / protein catabolic process at postsynapse / Noncanonical activation of NOTCH3 / TGFBR3 PTM regulation / 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 / dorsal/ventral neural tube patterning / regulation of synaptic vesicle cycle / neural retina development / L-glutamate import across plasma membrane / myeloid dendritic cell differentiation / Regulated proteolysis of p75NTR / metanephros development / regulation of phosphorylation / locomotion / brain morphogenesis / endoplasmic reticulum calcium ion homeostasis / nuclear outer membrane / amyloid precursor protein metabolic process / smooth endoplasmic reticulum calcium ion homeostasis / regulation of long-term synaptic potentiation / astrocyte activation involved in immune response / regulation of canonical Wnt signaling pathway / embryonic limb morphogenesis / aggresome / cell fate specification / skeletal system morphogenesis / glutamate receptor signaling pathway / myeloid cell homeostasis / azurophil granule membrane / regulation of postsynapse organization / ciliary rootlet / 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 / positive regulation of dendritic spine development / positive regulation of receptor recycling / adult behavior / blood vessel development / regulation of neuron projection development / heart looping / amyloid precursor protein catabolic process / cerebral cortex cell migration / protein glycosylation / amyloid-beta formation / negative regulation of apoptotic signaling pathway / membrane protein ectodomain proteolysis / endopeptidase activator activity / autophagosome assembly / 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 / Nuclear signaling by ERBB4 / T cell proliferation / 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 / positive regulation of glycolytic process / cellular response to calcium ion / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / cerebellum development / post-embryonic development / thymus development / epithelial cell proliferation / negative regulation of protein phosphorylation / dendritic shaft / apoptotic signaling pathway / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / PDZ domain binding / neuron migration
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 / Nicastrin small lobe / Presenilin/signal peptide peptidase / Presenilin, signal peptide peptidase, family
Similarity search - Domain/homology
CHOLESTEROL / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / : / Presenilin-1 / Nicastrin / Gamma-secretase subunit APH-1A / Gamma-secretase subunit PEN-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.4 Å
AuthorsGuo, X. / Li, H. / Kai, U. / Yan, C. / Lei, J. / Zhou, R. / Shi, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Basic Research Program of China (973 Program)2020YFA0509300 China
CitationJournal: To Be Published
Title: Structural Basis of gamma-secretase inhibition by anti-cancer clinical drugs
Authors: Guo, X. / Li, H. / Kai, U. / Yan, C. / Lei, J. / Zhou, R. / Shi, Y.
History
DepositionAug 8, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 14, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Nov 20, 2024Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / em_admin ...chem_comp / em_admin / entity / pdbx_entity_nonpoly
Item: _chem_comp.name / _em_admin.last_update ..._chem_comp.name / _em_admin.last_update / _entity.pdbx_description / _pdbx_entity_nonpoly.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nicastrin
B: Presenilin-1
C: Gamma-secretase subunit APH-1A
D: Gamma-secretase subunit PEN-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)179,04922
Polymers171,3924
Non-polymers7,65718
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Nicastrin


Mass: 77622.617 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NCSTN, KIAA0253, UNQ1874/PRO4317 / Production host: Homo sapiens (human) / References: UniProt: Q92542
#2: Protein Presenilin-1 / PS-1 / Protein S182


Mass: 52713.535 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PSEN1, AD3, PS1, PSNL1 / Production host: Homo sapiens (human)
References: UniProt: P49768, Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases

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Gamma-secretase subunit ... , 2 types, 2 molecules CD

#3: Protein Gamma-secretase subunit APH-1A / APH-1a / Aph-1alpha / Presenilin-stabilization factor


Mass: 29017.943 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APH1A, PSF, CGI-78, UNQ579/PRO1141 / Production host: Homo sapiens (human) / References: UniProt: Q96BI3
#4: Protein Gamma-secretase subunit PEN-2 / Presenilin enhancer protein 2


Mass: 12038.029 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PSENEN, PEN2, MDS033 / Production host: Homo sapiens (human) / References: UniProt: Q9NZ42

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Sugars , 3 types, 12 molecules

#5: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#6: Polysaccharide beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-3[DManpb1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2-2-2/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][b-D-Manp]{}[(6+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#7: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 3 types, 6 molecules

#8: Chemical ChemComp-PC1 / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 3-SN-PHOSPHATIDYLCHOLINE


Mass: 790.145 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM
#9: Chemical ChemComp-Q70 / Osugacestat


Mass: 556.500 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H26F6N4O3
Details: The depositor stated the chemical ligand bought from MCE (https://www.medchemexpress.cn/bms-906024.html).
Feature type: SUBJECT OF INVESTIGATION
#10: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cryo-EM structure of human gamma-secretase in complex with BMS906024
Type: COMPLEX / Entity ID: #1-#4 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 3306534 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00611148
ELECTRON MICROSCOPYf_angle_d0.97315247
ELECTRON MICROSCOPYf_dihedral_angle_d7.1676473
ELECTRON MICROSCOPYf_chiral_restr0.0581813
ELECTRON MICROSCOPYf_plane_restr0.0071846

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