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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 / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of endopeptidase activity / positive regulation of coagulation / 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 / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of endopeptidase activity / positive regulation of coagulation / 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 / negative regulation of axonogenesis / central nervous system myelination / membrane protein intracellular domain proteolysis / T cell activation involved in immune response / growth factor receptor binding / skin morphogenesis / choline transport / NOTCH4 Activation and Transmission of Signal to the Nucleus / dorsal/ventral neural tube patterning / regulation of resting membrane potential / neural retina development / 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 / astrocyte activation involved in immune response / embryonic limb morphogenesis / regulation of canonical Wnt signaling pathway / regulation of postsynapse organization / cell fate specification / skeletal system morphogenesis / aggresome / myeloid cell homeostasis / azurophil granule membrane / glutamate receptor signaling pathway / ciliary rootlet / positive regulation of dendritic spine development / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / Golgi cisterna membrane / positive regulation of amyloid fibril formation / G protein-coupled dopamine receptor signaling pathway / positive regulation of receptor recycling / regulation of neuron projection development / protein glycosylation / blood vessel development / adult behavior / mitochondrial transport / amyloid precursor protein catabolic process / heart looping / cerebral cortex cell migration / amyloid-beta formation / membrane protein ectodomain proteolysis / negative regulation of apoptotic signaling pathway / autophagosome assembly / negative regulation of ubiquitin-dependent protein catabolic process / EPH-ephrin mediated repulsion of cells / 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 / post-embryonic development / dendritic shaft / thymus development / positive regulation of glycolytic process / epithelial cell proliferation / PDZ domain binding / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / apoptotic signaling pathway / synapse organization / 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 large lobe / 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: Nat Struct Mol Biol / Year: 2024
Title: Structural basis of human γ-secretase inhibition by anticancer clinical compounds.
Authors: Xuefei Guo / Haotian Li / Xiaoli Lu / Hao Liu / Kaicheng U / Chuangye Yan / Jianlin Lei / Jing Huang / Rui Zhou / Yigong Shi /
Abstract: Aberrant activation of Notch signaling, mediated by the Notch intracellular domain (NICD), is linked to certain types of cancer. The NICD is released through γ-secretase-mediated cleavage of the ...Aberrant activation of Notch signaling, mediated by the Notch intracellular domain (NICD), is linked to certain types of cancer. The NICD is released through γ-secretase-mediated cleavage of the Notch receptor. Therefore, development of a γ-secretase inhibitor (GSI) represents an anticancer strategy. Here we report the cryo-electron microscopy structures of human γ-secretase bound individually to five clinically tested GSIs (RO4929097, crenigacestat, BMS906024, nirogacestat and MK-0752) at overall resolutions of 2.4-3.0 Å. Three of the five GSIs are in active anticancer clinical trials, while nirogacestat was recently approved. Each of these GSIs similarly occupies the substrate-binding site of presenilin 1 but shows characteristic differences in detailed recognition pattern. The size and shape of the binding pocket are induced by the bound GSI. Analysis of these structural features suggest strategies for modification of the GSI with improved inhibition potency.
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
Revision 1.3Dec 25, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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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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